Degradation Of Macromolecules Research Articles

Lysosomes accumulate at the perinuclear region of muscle cells during chick myogenesis.

Lysosomes are involved in a myriad of cellular functions, such as degradation of macromolecules, endocytosis and exocytosis, modulation of several signaling pathways, and regulation of cell metabolism. To fulfill these diverse functions, lysosomes can undergo several dynamic changes in their content, size, pH, and location within cells. Here, we studied some of these parameters during embryonic chick skeletal muscle cells. We used an anti-lysosome-associated membrane protein 2 (LAMP2) antibody to specifically determine the intracellular localization of lysosomes in these cells. Our data shows that lysosomes are highly enriched in the perinuclear region of chick embryonic muscle cells. We also showed that the wingless signaling pathway (Wnt)/β-catenin signaling pathway can modulate the location of LAMP2 in chick myogenic cells. Our results highlight the role of lysosomes during muscle differentiation and particularly the presence of a subcellular population of lysosomes that are concentrated in the perinuclear region of muscle cells.

Role of auxin and gibberellin under low light in enhancing saffron corm starch degradation during sprouting

The mechanisms by which low light accelerates starch macromolecules degradation by auxin and gibberellin (GA) in geophytes during sprouting remain largely unknown. This study investigated these mechanisms in saffron, grown under low light (50 μmol m−2 s−1) and optimal light (200 μmol m−2 s−1) during the sprouting phase. Low light reduced starch concentration in corms by 34.0 % and increased significantly sucrose levels in corms, leaves, and leaf sheaths by 19.2 %, 9.8 %, and 134.5 %, respectively. This was associated with a 33.3 % increase in GA3 level and enhanced auxin signaling. Leaves synthesized IAA under low light, which was transported to the corms to promote GA synthesis, facilitating starch degradation through a 228.7 % increase in amylase activity. Exogenous applications of GA and IAA, as well as the use of their synthesis or transport inhibitors, confirmed the synergistic role of these phytohormones in starch metabolism. The unigenes associated with GA biosynthesis and auxin signaling were upregulated under low light, highlighting the IAA-GA module role in starch degradation. Moreover, increased respiration rate and invertase activity, crucial for ATP biosynthesis and the tricarboxylic acid cycle, were consistent with the upregulation of related unigenes, suggesting that auxin signaling accelerates starch degradation by promoting energy metabolism. Upregulated of auxin signaling (CsSAUR32) and starch metabolism (CsSnRK1) genes under low light suggests that auxin directly regulate starch degradation in saffron corms. This study elucidates that low light modulates auxin and GA interactions to accelerate starch degradation in saffron corms during sprouting, offering insights for optimizing agricultural practices under suboptimal light conditions.

Balancing Maillard reaction products formation and antioxidant activities for improved sensory quality and health benefit properties of pan baked buns

This study investigated the impact of processing temperatures (190 °C, 210 °C, and 230 °C) and durations (7 min, 10 min, and 14 min) on the formation of Maillard reaction products (MRPs) and antioxidant activities in pan baked buns. Key Maillard reaction indicators, including glyoxal (GO), methylglyoxal (MGO), 5-hydroxymethylfurfural (5-HMF), melanoidins, and fluorescent advanced glycation end products (AGEs) were quantified. The results demonstrated significant increases in GO, MGO, 5-HMF contents (p < 0.05), and antioxidant activities (p < 0.05) when the buns were baked at 210 °C for 14 min, 230 °C for 10 min and 14 min. However, the interior MRPs of baked buns were minimally affected by the baking temperature and duration. Prolonged heating temperatures and durations exacerbated MRPs production (43.8 %–1038 %) in the bottom crust. Nonetheless, this process promoted the release of bound phenolic compounds and enhanced the antioxidant activity. Heating induces the thermal degradation of macromolecules in food, such as proteins and polysaccharides, which releases bound phenolic compounds by disrupting their chemical bonds within the food matrix. Appropriate selections of baking parameters can effectively reduce the formation of MRPs while simultaneously improve sensory quality and health benefit of the pan baked buns. Considering the balance between higher antioxidant properties and lower MRPs, the optimal thermal parameters for pan baked buns were 210 °C for 10 min. Furthermore, a normalized analysis revealed a consistent trend for GO, MGO, 5-HMF, fluorescent AGEs, and melanoidins. Moreover, MRPs were positively correlated with total contents of phenolic compounds, ferric-reducing antioxidant power (FRAP), and color, but negatively correlated with moisture contents and reducing sugars. Additionally, the interaction between baking conditions and Maillard reactions probably contributed to enhanced primary flavors in the final product. This study highlights the importance of optimizing baking parameters to achieve desirable MRPs levels, higher antioxidant activity, and optimal sensory attributes in baked buns.

Pollutant degradation and hydrogen production of landfill leachate membrane concentrates via aqueous phase reforming

Membrane filtration is a mainstream method for landfill leachate treatment, leaving the landfill leachate membrane concentrates (LLMCs) a high-toxicity residue. Conventional LLMCs disposal technology shows specific challenges due to the low biodegradability, high inorganic salts, and high heavy metal ions content of LLMCs. Therefore, it is necessary to degrade LLMCs with a more suitable technology. In this study, a special method was proposed to convert some organic chemicals into valuable compounds by aqueous phase reforming (APR). Ni-based catalysts (Ni//La2O3, Ni/CeO2, Ni/MgO, and Ni/Al2O3) were prepared to investigate the effect of different supports on the APR of LLMCs. APR performed outstanding characteristics in the decrease of chemical oxygen demand (COD) and total organic carbon (TOC), the degradation of macromolecules, and the removal of heavy metal ions in the aqueous phase. In addition, H2 was generated which is beneficial for energy compensating during the APR process. The best-performing catalyst (Ni/Al2O3) was selected to investigate the effects of reaction temperature, reaction time, and catalyst addition on product distribution. The optimal H2 selectivity (44.71%) and H2 production (11.63 mmol/g COD) were obtained at 250 °C with 2 g Ni/Al2O3 usage for 1 h. This paper provided a new perspective on the disposal of LLMCs, which will degrade pollutants efficiently.

Lysosomal biogenesis and function in osteoclasts: a comprehensive review.

Lysosomes serve as catabolic centers and signaling hubs in cells, regulating a multitude of cellular processes such as intracellular environment homeostasis, macromolecule degradation, intracellular vesicle trafficking and autophagy. Alterations in lysosomal level and function are crucial for cellular adaptation to external stimuli, with lysosome dysfunction being implicated in the pathogenesis of numerous diseases. Osteoclasts (OCs), as multinucleated cells responsible for bone resorption and maintaining bone homeostasis, have a complex relationship with lysosomes that is not fully understood. Dysregulated function of OCs can disrupt bone homeostasis leading to the development of various bone disorders. The regulation of OC differentiation and bone resorption for the treatment of bone disease have received considerable attention in recent years, yet the role and regulation of lysosomes in OCs, as well as the potential therapeutic implications of intervening in lysosomal biologic behavior for the treatment of bone diseases, remain relatively understudied. This review aims to elucidate the mechanisms involved in lysosomal biogenesis and to discuss the functions of lysosomes in OCs, specifically in relation to differentiation, bone resorption, and autophagy. Finally, we explore the potential therapeutic implication of targeting lysosomes in the treatment of bone metabolic disorders.

Lysosomal TBK1 responds to amino acid availability to relieve Rab7-dependent mTORC1 inhibition

Lysosomes play a pivotal role in coordinating macromolecule degradation and regulating cell growth and metabolism. Despite substantial progress in identifying lysosomal signaling proteins, understanding the pathways that synchronize lysosome functions with changing cellular demands remains incomplete. This study uncovers a role for TANK-binding kinase 1 (TBK1), well known for its role in innate immunity and organelle quality control, in modulating lysosomal responsiveness to nutrients. Specifically, we identify a pool of TBK1 that is recruited to lysosomes in response to elevated amino acid levels. This lysosomal TBK1 phosphorylates Rab7 on serine 72. This is critical for alleviating Rab7-mediated inhibition of amino acid-dependent mTORC1 activation. Furthermore, a TBK1 mutant (E696K) associated with amyotrophic lateral sclerosis and frontotemporal dementia constitutively accumulates at lysosomes, resulting in elevated Rab7 phosphorylation and increased mTORC1 activation. This data establishes the lysosome as a site of amino acid regulated TBK1 signaling that is crucial for efficient mTORC1 activation. This lysosomal pool of TBK1 has broader implications for lysosome homeostasis, and its dysregulation could contribute to the pathogenesis of ALS-FTD.

Diosmetin ameliorates osteoarthritic inflammation in vivo and ECM macromolecules degradation in interleukin-1β-stimulated murine chondrocytes through the Nrf2/NF-κB pathway.

Osteoarthritis (OA) is a prevailing degenerative disease in elderly population and can lead to severe joint dysfunction. Studies have revealed various pharmacological activities of diosmetin, including the anti-OA efficacy. The present study further investigated its effect on interleukin (IL)-1β-induced OA in chondrocytes. Primary chondrocytes were isolated from young mice, stimulated with IL-1β (10 ng/mL), and pretreated with diosmetin (10 and 20 μM) to conduct the in vitro assays. CCK-8 assay assessed the cytotoxicity of diosmetin whereas the levels of inflammatory factors (PGE2, nitrite, TNF-α, and IL-6) in homogenized cells were evaluated by ELISA. The levels of inflammatory cytokines, content of extracellular matrix (ECM), and signaling-related proteins (Nrf2, HO-1, and NF-κB p65) were assessed by western blotting. Expression of collagen II, p65, and Nrf2 in the chondrocytes was confirmed by immunofluorescence staining. The chondrocytes treated with IL-1β and diosmetin were transfected with Nrf2 knockdown plasmid (si-Nrf2) to investigate the role of Nrf2. In vivo OA mouse model was induced by surgically destabilizing the medial meniscus (DMM). Safranin O staining was conducted to assess the OA severity in the knee-joint tissue. Diosmetin suppressed the expression of iNOS, COX-2, PGE2, nitrite, TNF-α, IL-6, MMP-13, and ADAMTS-5 induced by IL-1β in chondrocytes. The expression of p-p65, p-IκBα, and nuclear p65 was decreased whereas that of Nrf2 and HO-1 increased by diosmetin treatment in IL-1β-treated chondrocytes. Nrf2 knockdown by siRNA reversed the inhibitory effect of diosmetin on IL-1β-induced degradation of ECM proteins and inflammatory factors in cultured chondrocytes. In the DMM-induced model of OA, diosmetin alleviated cartilage degeneration and decreased the Osteoarthritis Research Society International score. Diosmetin ameliorates expression of inflammation biomarkers and ECM macromolecules degradation in cultured murine chondrocytes via inactivation of NF-κB signaling by activating Nrf2/HO-1 signaling pathway.

The effect of L-cysteine on starch and protein degradation during barley germination.

In order to investigate the impact of L-cysteine (L-Cys) on starch and protein degradation during barley germination. The amylase activities, degradation of macromolecules during germination were determined in this study. Barley was germinated in petri dish for 0 to 5days with different levels of L-Cys (0mM, 2.5mM, 5mM, 10mM). L-Cys addition increased the total limit dextrinase (LD) activities and decreased the LD inhibitor activities during whole germination stage. The activities of α-amylase, β-amylase and free LD were increased with the addition of 2.5, 5mM L-Cys at germination days 1 to 4. Due to higher amylase in malt with the addition of L-Cys, the non-fermentable sugars were reduced and the glucose, maltotriose were improved. Furthermore, the protein degradation analysis showed that low molecular weight protein increased and middle molecular weight protein decreased obviously in wort from the malt germinated with L-Cys, demonstrating that the L-Cys promote the protein degradation. Lastly, the filtration performance of malt with the addition of L-Cys during malting was better than the control. In conclusion, L-Cys can promote the degradation of storage material (starch, protein) during barley germination, leading to a better green malt quality.

MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes

The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1–GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1–GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.

Functional divergences of natural variations of TaNAM-A1 in controlling leaf senescence during wheat grain filling.

Leaf senescence is an essential physiological process related to grain yield potential and nutritional quality. Green leaf duration (GLD) after anthesis directly reflects the leaf senescence process and exhibits large genotypic differences in common wheat; however, the underlying gene regulatory mechanism is still lacking. Here, we identified TaNAM-A1 as the causal gene of the major loci qGLD-6A for GLD during grain filling by map-based cloning. Transgenic assays and TILLING mutant analyses demonstrated that TaNAM-A1 played a critical role in regulating leaf senescence, and also affected spike length and grain size. Furthermore, the functional divergences among the three haplotypes of TaNAM-A1 were systematically evaluated. Wheat varieties with TaNAM-A1d (containing two mutations in the coding DNA sequence of TaNAM-A1) exhibited a longer GLD and superior yield-related traits compared to those with the wild type TaNAM-A1a. All three haplotypes were functional in activating the expression of genes involved in macromolecule degradation and mineral nutrient remobilization, with TaNAM-A1a showing the strongest activity and TaNAM-A1d the weakest. TaNAM-A1 also modulated the expression of the senescence-related transcription factors TaNAC-S-7A and TaNAC016-3A. TaNAC016-3A enhanced the transcriptional activation ability of TaNAM-A1a by protein-protein interaction, thereby promoting the senescence process. Our study offers new insights into the fine-tuning of the leaf functional period and grain yield formation for wheat breeding under various geographical climatic conditions.

Evaluation of the impact of natural weathering on the properties of high‐density polyethylene bottles by experimental approach

AbstractThis work presents an in‐depth experimental study aimed at assessing the impact of natural weathering on the behavior of high‐density polyethylene (HDPE) bottles. To this end, several analytical techniques were employed, including Fourier transform infrared spectroscopy (FTIR) to examine molecular changes, scanning electron microscopy (SEM) to study morphology, thermogravimetric analysis (TGA) to assess thermal properties, and tensile and compression tests to evaluate mechanical properties. The results obtained reveal significant changes in HDPE exposed to natural weathering. FTIR analysis enabled us to identify that the HDPE bottles had been subjected to an oxidation process initiated by the absorption of solar radiation during natural weathering treatments, while SEM analysis showed the presence of holes resulting from the detachment of material fragments after exposure, TGA analysis confirms the impact of natural exposure time on the decrease in the average molecular weight and chemical degradation of HDPE macromolecules, through a reduction in the initial degradation temperature and the maximum thermodegradation temperature. However, tensile and compressive tests showed a reduction in the mechanical strength of HDPE after exposure to natural conditions, with notable variations depending on environmental conditions, making the material damaged. These results enabled us to calculate the damage caused by three damage laws. These results offer important insights into the mechanisms of HDPE degradation under the influence of natural climatic factors, paving the way for the development of more resistant and durable packaging materials in the face of variable environmental conditions.Highlights The objective of this study is to analyze and describe the effects of natural weathering on high‐density polyethylene bottles. This involves evaluating the deterioration of physicochemical, mechanical, and morphological properties. Additionally, three damage laws are employed to assess the extent of damage inflicted by this material. Analytical techniques were used, including SEM, FTIR, and TGA, tensile and compressive test.

Gaining insight into the effect of laccase expression on humic substance formation during lignocellulosic biomass composting

The aim is to enhance lignin humification by promoting laccase activities which can promote lignin depolymerization and reaggregation during composting. 1-Hydroxybenzotriazole (HBT) is employed to conduct laccase mediator system (LMS), application of oxidized graphene (GO) in combination to strengthen LMS. Compared with control, the addition of GO, HBT, and GH (GO coupled with HBT) significantly improved laccase expression and activities (P < 0.05), with lignin humification efficiency also increased by 68.6 %, 36.7 %, and 107.8 %. GH treatment induces microbial expression of laccase by increasing the abundance and synergy of core microbes. The unsupervised learning model, vector autoregressive model and Mantel test function were combined to elucidate the mechanism of action of exogenous materials. The results showed that GO stabilized the composting environment on the one hand, and acted as a support vector to stabilize the LMS and promote the function of laccase on the other. In GH treatment, degradation of macromolecules and humification of small molecules were promoted simultaneously by activating the dual function of laccase. Additionally, it also reveals the GH enhances the humification of lignocellulosic compost by converting phenolic pollutants into aggregates. These findings provide a new way to enhance the dual function of laccase and promote lignin humification during composting. It could effectively achieve the resource utilization of organic solid waste and reduce composting pollution.

Kinetics of Radiation–Oxidative Aging of HDPE Fibers with Simultaneous Degradation and Crosslinking of Macromolecules

Kinetics of Radiation–Oxidative Aging of HDPE Fibers with Simultaneous Degradation and Crosslinking of Macromolecules

Multi-focused laboratory experiments based on Quorum Sensing and Quorum Quenching for acquiring Microbial Physiology concepts.

After a time away from the classrooms and laboratories due to the global pandemic, the return to teaching activities during the semester represented a challenge to both teachers and students. Our particular situation in a Microbial Physiology course was the necessity of imparting in shorter time, laboratory practices that usually take longer. This article describes a 2-week-long laboratory exercise that covers several concepts in an interrelated way: conjugation as a gene transfer mechanism, regulation of microbial physiology, production of secondary metabolites, degradation of macromolecules, and biofilm formation. Utilizing a Quorum Quenching (QQ) strategy, the Quorum Sensing (QS) system of Pseudomonas aeruginosa is first attenuated. Then, phenotypes regulated by QS are evidenced. QS is a regulatory mechanism of microbial physiology that relies on signal molecules. QS is related in P. aeruginosa to several virulence factors, some of which are exploited in the laboratory practices presented in this work. QQ is a phenomenon by which QS is interrupted or attenuated. We utilized a QQ approach based on the enzymatic degradation of the P. aeruginosa QS signals to evidence QS-regulated traits that are relevant to our Microbial Physiology course. Results obtained with the same test performed by a random group of students before and after the activities show the positive effectiveness of the approach presented in this work.

Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.

Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

Cleavage of Hsp70.1 causes lysosomal cell death under stress conditions.

Autophagy mediates the degradation of intracellular macromolecules and organelles within lysosomes. There are three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Heat shock protein 70.1 (Hsp70.1) exhibits dual functions as a chaperone protein and a lysosomal membrane stabilizer. Since chaperone-mediated autophagy participates in the recycling of ∼30% cytosolic proteins, its disorder causes cell susceptibility to stress conditions. Cargo proteins destined for degradation such as amyloid precursor protein and tau protein are trafficked by Hsp70.1 from the cytosol into lysosomes. Hsp70.1 is composed of an N-terminal nucleotide-binding domain (NBD) and a C-terminal domain that binds to cargo proteins, termed the substrate-binding domain (SBD). The NBD and SBD are connected by the interdomain linker LL1, which modulates the allosteric structure of Hsp70.1 in response to ADP/ATP binding. After the passage of the Hsp70.1-cargo complex through the lysosomal limiting membrane, high-affinity binding of the positive-charged SBD with negative-charged bis(monoacylglycero)phosphate (BMP) at the internal vesicular membranes activates acid sphingomyelinase to generate ceramide for stabilizing lysosomal membranes. As the integrity of the lysosomal limiting membrane is critical to ensure cargo protein degradation within the acidic lumen, the disintegration of the lysosomal limiting membrane is lethal to cells. After the intake of high-fat diets, however, β-oxidation of fatty acids in the mitochondria generates reactive oxygen species, which enhance the oxidation of membrane linoleic acids to produce 4-hydroxy-2-nonenal (4-HNE). In addition, 4-HNE is produced during the heating of linoleic acid-rich vegetable oils and incorporated into the body via deep-fried foods. This endogenous and exogenous 4-HNE synergically causes an increase in its serum and organ levels to induce carbonylation of Hsp70.1 at Arg469, which facilitates its conformational change and access of activated μ-calpain to LL1. Therefore, the cleavage of Hsp70.1 occurs prior to its influx into the lysosomal lumen, which leads to lysosomal membrane permeabilization/rupture. The resultant leakage of cathepsins is responsible for lysosomal cell death, which would be one of the causative factors of lifestyle-related diseases.

Degradation and mechanism analysis of protein macromolecules by functional bacteria in tobacco leaves.

Tobacco, a crop of significant economic importance, was greatly influenced in leaf quality by protein content. However, current processing parameters fail to adequately meet the requirements for protein degradation. Microorganisms possess potential advantages for degrading proteins and enhancing the quality of tobacco leaves, and hold substantial potential in the process of curing. To effectively reduce the protein content in tobacco leaves, thereby improving the quality and safety of the tobacco leaves. In this study, tobacco leaf were used as experimental material. From these, the BSP1 strain capable of effectively degrading proteins was isolated and identified as Bacillus subtilis by 16S rDNA analysis. Furthermore, the mechanisms were analyzed by integrating microbiome, transcriptome, and metabolome. Before curing, BSP1 was applied to the surface of tobacco leaves. The results indicated that BSP1 effectively improves the activity of key enzymes and the content of related substances, thereby enhancing protein degradation. Additionally, protein degradation was achieved by regulating the diversity of the microbial community on the surface of the tobacco leaves and the ubiquitin-proteasome pathway. This study provided new strategies for extracting and utilizing functional strains from tobacco leaves, opening new avenues for enhancing the quality of tobacco leaves.

- Invited Review - Understanding the functionality of the rumen microbiota: searching for better opportunities for rumen microbial manipulation.

Rumen microbiota play a central role in the digestive process of ruminants. Their remarkable ability to break down complex plant fibers and proteins, converting them into essential organic compounds that provide animals with energy and nutrition. Research on rumen microbiota not only contributes to improving animal production performance and enhancing feed utilization efficiency but also holds the potential to reduce methane emissions and environmental impact. Nevertheless, studies on rumen microbiota face numerous challenges, including complexity, difficulties in cultivation, and obstacles in functional analysis. This review provides an overview of microbial species involved in the degradation of macromolecules, the fermentation processes, and methane production in the rumen, all based on cultivation methods. Additionally, the review introduces the applications, advantages, and limitations of emerging omics technologies such as metagenomics, metatranscriptomics, metaproteomics, and metabolomics, in investigating the functionality of rumen microbiota. Finally, the article offers a forward-looking perspective on the new horizons and technologies in the field of rumen microbiota functional research. These emerging technologies, with continuous refinement and mutual complementation, have deepened our understanding of rumen microbiota functionality, thereby enabling effective manipulation of the rumen microbial community.

The PB1 and the ZZ domain of the autophagy receptor p62/SQSTM1 regulate the interaction of p62/SQSTM1 with the autophagosome protein LC3B.

Autophagy is a highly conserved cellular process that allows degradation of large macromolecules. p62/SQSTM1 is a key adaptor protein that interacts both with material to be degraded and with LC3 at the autophagosome, enabling degradation of cargos such as protein aggregates, lipid droplets and damaged organelles by selective autophagy. Dysregulation of autophagy contributes to the pathogenesis of many diseases. In this study, we investigated if the interaction of p62/SQSTM1 with LC3B could be regulated. We purified full-length p62/SQSTM1 and established an in vitro assay that measures the interaction with LC3B. We used the assay to determine the role of the different domains of p62/SQSTM1 in the interaction with LC3B. We identified a mechanism of regulation of p62/SQSTM1 where the ZZ and the PB1 domains regulate the exposure of the LIR-sequence to enable or inhibit the interaction with LC3B. A mutation to mimic the phosphorylation of a site on the ZZ domain leads to increased interaction with LC3B. Also, a small compound that binds to the ZZ domain enhances interaction with LC3B. Dysregulation of these mechanisms in p62/SQSTM1 could have implications for diseases where autophagy is affected. In conclusion, our study highlights the regulated nature of p62/SQSTM1 and its ability to modulate the interaction with LC3B through a LIR-sequence Accessibility Mechanism (LAM). Furthermore, our findings suggest the potential for pharmacological modulation of the exposure of LIR, paving the way for future therapeutic strategies.

Unveiling autophagy complexity in leukemia: The molecular landscape and possible interactions with apoptosis and ferroptosis

Autophagy is a self-digestion multistep process in which causes the homeostasis through degradation of macromolecules and damaged organelles. The autophagy-mediated tumor progression regulation has been a critical point in recent years, revealing the function of this process in reduction or acceleration of carcinogenesis. Leukemia is a haematological malignancy in which abnormal expansion of hematopoietic cells occurs. The current and conventional therapies from chemotherapy to cell transplantation have failed to appropriately treat the leukemia patients. Among the mechanisms dysregulated in leukemia, autophagy is a prominent one in which can regulate the hallmarks of this tumor. The protective autophagy inhibits apoptosis and ferroptosis in leukemia, while toxic autophagy accelerates cell death. The proliferation and invasion of tumor cells are tightly regulated by the autophagy. The direction of regulation depends on the function of autophagy that is protective or lethal. The protective autophagy accelerates chemoresistance and radio-resistsance. The non-coding RNAs, histone transferases and other pathways such as PI3K/Akt/mTOR are among the regulators of autophagy in leukemia progression. The pharmacological intervention for the inhibition or induction of autophagy by the compounds including sesamine, tanshinone IIA and other synthetic compounds can chance progression of leukemia.