Rescue Mechanism Research Articles

Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia

Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.

Transcriptomics reveals that the caudal neurosecretory system in the olive flounder (Paralichthys olivaceus) is more responsive in bold individuals and to chronic temperature change

In farmed animals, personalities have demonstrated links to performance traits, health and welfare, disease susceptibility, and to coping with environmental stress. The teleost caudal neurosecretory system (CNSS) of the posterior spinal cord is involved in the regulation of the osmoregulatory and stress responses and can directly sense a hypothermal challenge via a transient receptor potential ion channel. Here we investigated the global transcriptomic response of the CNSS of shy and bold individuals of the olive flounder (Paralichthys olivaceus) acclimated to 18 °C and transferred to 12 °C (low temperature treatment, LT) or 24 °C (high temperature treatment, HT) for 2 h (acute) or 8 days (chronic) in relation to fish maintained at 18 °C (control). Overall, differential transcriptomic responses were stronger in bold individuals and induced by acute HT and chronic LT treatments. Acute HT induced innate immunity, circadian rhythm, and cellular stress response pathways and, specifically in bold individuals, a heightened response of molecular chaperones of cellular response to heat which may be related to the mechanisms of rescue of downregulated RNA splicing processes. Chronic LT also caused downregulation of innate immunity pathways as well as pathways related to cell division. In addition, the CNSS of bold individuals was enriched in pathways related to regulation of cell cycle, adaptive immune response, and apoptosis, while cellular metabolism pathways were downregulated in shy individuals. The putative temperature sensor genes Trpv1 and Trpa1 were upregulated, respectively, after acute HT and chronic LT treatments, but there was no indication of a specific neurosecretory response of the CNSS. While several of the observed transcriptomic responses to temperature appear to be shared by other tissues and species, it is also clear that bold and shy behavioural personalities show marked different responses, with bold individuals the most responsive. These results add to the knowledge base available on olive flounder aquaculture, indicating a differential role of the CNSS in the response to temperature change according to behavioural personalities.

Activation of Insulin-Like Growth Factor-2 Ameliorates Retinal Cell Damage and Exerts Protection in in vitro Model of Diabetic Retinopathy

Background: The major event in the development of diabetes-related blindness and vision impairment is the onset of retinal cell damage. Overall awareness of insulin-like growth factor-2 (IGF2) mechanisms emphasizes its protective behavior in retinal cells that help to provide new information about the development of treatment for retinal complications. Objectives: This study analyzes the effect of in vitro changes associated with the cell survival and rescue mechanism in IGF2 inhibition and activation using chromeceptin and IGF2 peptides in ARPE-19 cells cultured in high glucose conditions. Method: Cell death was induced using high glucose (15 mmol/L), IGF2 inhibition was done using chromeceptin (1 µM) (Sigma Aldrich, Saint Louis, MO, USA), and IGF2 activation was done using IGF2 peptide (10 ng/mL). The cells were analyzed for changes in cell proliferation, apoptosis markers, antioxidant molecules, and alteration of cytokines. Results: The study demonstrated that cells lacking IGF2 exhibited a significant increase in reactive oxygen levels with apoptosis patterns. Also, gene expression analysis by qRT-PCR demonstrated a significant increase in Yes-associated protein 1, CDK2, TNF-α, and BIRC5 genes in cells under high glucose stress and IGF inhibition compared to control. Further, the cytokine analysis also revealed that cells devoid of IGF2 activated an increase in cytokines such as IL-8, CX43, ICAM-1, IL-17, CCL3, and MCP-1 and decreased paraoxonase compared to normal control cells. On the other hand, ARPE-19 cells grown in high glucose shows that IGF2 increases the survival genes with reduced levels of inflammatory cytokines. Conclusion: The finding of the investigation, therefore, shows that the use of IGF2 activators may prevent the progression of ocular dysfunction in the control of diabetes-related complications.

Ensemble simulations: folding, unfolding and misfolding of high‐efficiency transfer‐messenger RNA pseudoknot

The PK1 pseudoknot, a well-characterized super secondary structure, from Aquifex aeolicus is a transfer-messenger RNA (tmRNA) that participates in the ribosomal trans-translation rescue mechanism. Extensive all-atom molecular dynamics simulations were conducted across a worldwide distributed computing network to study the folding, unfolding, misfolding and conformational plasticity of the twenty-two nucleotides PK1 pseudoknot, yielded nearly 140 µs of cumulative sampling time. Complex K-means clustering was utilized to identify twenty-seven conformational microstates among forty starting structures spanning from the extended unfolded state to the native fold. Moreover, post equilibration data, established at 7.5 ns, provided detailed depictions the conformational free energy landscape that encompass the native states, numerous intermediate and misfolded states and intricate folding mechanism of the pseudoknot motif. The PK1 pseudoknot displays structural similarities to the class of frameshifting pseudoknots and suggests a parallel between the trans-translational mechanism and frameshifting mechanism of our previous study of the potato lead roll virus RNA pseudoknot.

A New Career Opportunity As An Insolvency Practitioner In Malaysia Under The Companies Act 2016

The Companies Act 2016 is now the legal framework that regulates the law and practices of companies that are incorporated under this Act. It repealed the previous Companies Act 1965 after five decades later. The CA 2016 came into force on 31st January 2017 and became operational on that date. It comprises 620 sections and 13 schedules and it is the result of the strenuous study by the Corporate Law Reform Committee (“CLRC”) which was established by the Companies Commission of Malaysia and had undertaken the review of the 1965 Act. CLRC was part of the CCM’s strategic direction initiatives formulated in 2003 to develop a dynamic and conducive environment for business in Malaysia.The 2016 Act has brought in the modernizing of Insolvency Law by introducing Corporate Rescue Mechanisms to revive financially troubled companies, restructuring the concept of scheme of arrangements between a company and its creditors and refining the role of receivers/receivers & managers. The 2016 Act has also decoupled the requirement for an approved liquidator to be an approved auditor as under the old Act, it requires the approved liquidator to hold an audit licence before he or she can apply for a liquidator’s licence.Under Section 433(3) of CA 2016, any person who is a member of a recognised professional body may apply to the Minister of Finance to be approved as a liquidator. The Minister of Finance may approve such a person as a liquidator if he is satisfied with the experience and capacity of the person and upon payment of the prescribed fee by such a person. The minister, in consultation with the Minister of Finance has prescribed Malaysian Institute of Accountants (“MIA”) and Malaysian Institute of Certified Public Accountants (“MICPA”) as recognised professional bodies with effect from 15th March 2018.According to the statistics of liquidators as at 31 December 2018 compiled by the MIA, there are 197 Chartered Accountants who are in possession of liquidators’ licences. Out of these 197, a total of 143 or 73% are aged 60 to 81 and above. This means that when these approved liquidators retire at age 60 and above, there are 54 approved liquidators left who may not be in active practice. The statistics revealed that there is an acute shortage of approved liquidators in Malaysia. These liquidators would not be able to cope with handling the huge number of companies that have gone into compulsory liquidation, which at present stand at 42,406 from 2009 to 2019 of which 25,950 cases are being handled by the Official Receiver. With the limited resources at the Official Receiver’s offices nationwide, it proves that it would take a long time for the Official Receiver to complete the winding up of the affairs of the wound up companies.The 2016 Act has opened the door for a chartered accountant of MIA or Certified Public Accountant to apply directly for liquidator’s licence without the need to possess an audit licence 1st. This paper will deal with the various types of appointment which an insolvency practitioner can act, the basis of their remuneration, the authority that supervises their conduct in handling the affairs of the wound up companies, the various networks which the insolvency practitioner can build their network and the areas in which the industrial revolution 4.0 has disrupted businesses which can have an impact on the values of the property or assets to be disposed of.

Reflection on Emergency Management in China Based on Novel Coronavirus Pneumonia Prevention and Control

In 2019, China had novel coronavirus pneumonia outbreak in Wuhan, China, which seriously threatened people’s health and affected social order and economic development. The novel coronavirus epidemic has been actively dealt with by the government. However, there are still some problems, such as weak awareness of crisis, ineffective emergency response, stagnant legal construction, unsound rumors, ineffective public opinion, insufficient material support, inefficient allocation of resources, the local officials with low ability, inadequate humanistic care and incomplete rescue mechanism. By analyzing how the government deal with the novel coronavirus pneumonia crisis, we can optimize the working mechanism, improving the working methods, and improving the government’s emergency management capability.

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila.

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/IGF signalling is reduced in fly models of C9orf72 repeat expansion using RNA sequencing of adult brain. We further demonstrate that activation of insulin/IGF signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/IGF signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/IGF signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.

Prenatal diagnosis of 7 cases with uniparental disomy by utilization of single nucleotide polymorphism array

BackgroundThe phenotypes of uniparental disomy (UPD) are variable, which may either have no clinical impact, lead to clinical signs and symptoms. Molecular analysis is essential for making a correct diagnosis. This study involved a retrospective analysis of 4512 prenatal diagnosis samples and explored the molecular characteristics and prenatal phenotypes of UPD using a single nucleotide polymorphism (SNP) array.ResultsOut of the 4512 samples, a total of seven cases of UPD were detected with an overall frequency of 0.16%. Among the seven cases of UPD, two cases are associated with chromosomal aberrations (2/7), four cases (4/7) had abnormal ultrasonographic findings. One case presented with iso-UPD (14), and two case presented with mixed hetero/iso-UPD (15), which were confirmed by Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as maternal UPD (15) associated with Prader-Willi syndrome (PWS). Four cases had iso-UPD for chromosome 1, 3, 14, and 16, respectively; this is consistent with the monosomy rescue mechanism. Another three cases presented with mixed hetero/isodisomy were consistent with a trisomy rescue mechanism.ConclusionThe prenatal phenotypes of UPD are variable and molecular analysis is essential for making a correct diagnosis and genetic counselling of UPD. The SNP array is a useful genetic test in prenatal diagnosis cases with UPD.

Risk warning technologies and emergency response mechanisms in Sichuan—Tibet Railway construction

Safety is one of the most critical themes in any large-scale railway construction project. Recognizing the importance of safety in railway engineering, practitioners and researchers have proposed various standards and procedures to ensure safety in construction activities. In this study, we first review four critical research areas of risk warning technologies and emergency response mechanisms in railway construction, namely, (i) risk identification methods of large-scale railway construction projects, (ii) risk management of large-scale railway construction, (iii) emergency response planning and management, and (iv) emergency response and rescue mechanisms. After reviewing the existing studies, we present four corresponding research areas and recommendations on the Sichuan-Tibet Railway construction. This study aims to inject new significant theoretical elements into the decision-making process and construction of this railway project in China.

Ensemble Simulations: Folding, Unfolding and Misfolding of High-Efficiency Transfer-Messenger RNA Pseudoknot

The PK1 pseudoknot is a well-characterized super secondary structure from Aquifex aeolicus transfer-messenger RNA that participates in the ribosomal trans-translation rescue mechanism. Extensive all-atom molecular dynamics simulations were conducted across a worldwide distributed computing network to study the folding, unfolding, misfolding, and conformational plasticity of the twenty-two nucleotide PK1 pseudoknot, yielding nearly 120 µs of cumulative sampling time. Identification of native and non-native contacts throughout the resulting data set was used as input for k-means clustering, which detected twenty-seven conformational microstates sampled from forty starting structures that span the spectrum between the native fold and the fully denatured state.

Mountain Disasters and Rescue Mechanism in Nepal

Geographically, Nepal is divided into three regions, namely; the Terai, the hills, and the mountains. Nepal is prone to many types of disasters due to the various causes and one of the main causes is its geographic setting. Some disasters and hazards are prevalent to all over the country, some are area specific. Mountain and high altitude hazards are unique in nature and have distinct features and they pose several challenges for the rescue and relief operations. Disasters in mountain regions of Nepal have multi-dimensional effects on human life, property and the environment. The paper analyzes the mountain disasters, their nature and their impacts. It also focuses on the institutional as well as legal arrangements regarding disaster rescue. For this purpose, a qualitative descriptive and analytical method is applied to achieve the desired objectives of the study. This paper depends upon the secondary source of data available in several works of literature; journal articles, books, news articles, government reports, and websites. The paper finds that the frequencies of mountain disasters are low in comparison to other parts of Nepal, but they are diverse and complex. There are institutional and legal mechanisms for disaster risk reduction, but they are not adequate to respond mountain disasters effectively. All security agencies along with private sectors involving in mountain search and rescue operations do not have sufficient mountain-specific rescue units, training, and logistics.

Defective Autophagy and Mitophagy in Aging and Alzheimer's Disease.

Aging is the time-dependent process that all living organisms go through characterized by declining physiological function due to alterations in metabolic and molecular pathways. Many decades of research have been devoted to uncovering the cellular changes and progression of aging and have revealed that not all organisms with the same chronological age exhibit the same age-related declines in physiological function. In assessing biological age, factors such as epigenetic changes, telomere length, oxidative damage, and mitochondrial dysfunction in rescue mechanisms such as autophagy all play major roles. Recent studies have focused on autophagy dysfunction in aging, particularly on mitophagy due to its major role in energy generation and reactive oxidative species generation of mitochondria. Mitophagy has been implicated in playing a role in the pathogenesis of many age-related diseases, including Alzheimer’s disease (AD), Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. The purpose of our article is to highlight the mechanisms of autophagy and mitophagy and how defects in these pathways contribute to the physiological markers of aging and AD. This article also discusses how mitochondrial dysfunction, abnormal mitochondrial dynamics, impaired biogenesis, and defective mitophagy are related to aging and AD progression. This article highlights recent studies of amyloid beta and phosphorylated tau in relation to autophagy and mitophagy in AD.

Atomic-scale insights into allosteric inhibition and evolutional rescue mechanism of Streptococcus thermophilus Cas9 by the anti-CRISPR protein AcrIIA6

CRISPR-Cas systems are prokaryotic adaptive immunity against invading phages and plasmids. Phages have evolved diverse protein inhibitors of CRISPR-Cas systems, called anti-CRISPR (Acr) proteins, to neutralize this CRISPR machinery. In response, bacteria have co-evolved Cas variants to escape phage’s anti-CRISPR strategies, called anti-anti-CRISPR systems. Here we explore the anti-CRISPR allosteric inhibition and anti-anti-CRISPR rescue mechanisms between Streptococcus thermophilus Cas9 (St1Cas9) and the anti-CRISPR protein AcrIIA6 at the atomic level, by generating mutants of key residues in St1Cas9. Extensive unbiased molecular dynamics simulations show that the functional motions of St1Cas9 in the presence of AcrIIA6 differ substantially from those of St1Cas9 alone. AcrIIA6 binding triggers a shift of St1Cas9 conformational ensemble towards a less catalytically competent state; this state significantly compromises protospacer adjacent motif (PAM) recognition and nuclease activity by altering interdependently conformational dynamics and allosteric signals among nuclease domains, PAM-interacting (PI) regions, and AcrIIA6 binding motifs. Via in vitro DNA cleavage assays, we further elucidate the rescue mechanism of efficiently escaping AcrIIA6 inhibition harboring St1Cas9 triple mutations (G993K/K1008M/K1010E) in the PI domain and identify the evolutionary landscape of such mutational escape within species. Our results provide mechanistic insights into Acr proteins as natural brakes for the CRISPR-Cas systems and a promising potential for the design of allosteric Acr peptidomimetics.

Quality Control Mechanisms in Bacterial Translation.

Ribosome stalling during translation significantly reduces cell viability, because cells have to spend resources on the synthesis of new ribosomes. Therefore, all bacteria have developed various mechanisms of ribosome rescue. Usually, the release of ribosomes is preceded by hydrolysis of the tRNA–peptide bond, but, in some cases, the ribosome can continue translation thanks to the activity of certain factors. This review describes the mechanisms of ribosome rescue thanks to trans-translation and the activity of the ArfA, ArfB, BrfA, ArfT, HflX, and RqcP/H factors, as well as continuation of translation via the action of EF-P, EF-4, and EttA. Despite the ability of some systems to duplicate each other, most of them have their unique functional role, related to the quality control of bacterial translation in certain abnormalities caused by mutations, stress cultivation conditions, or antibiotics.

Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine

Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast, Saccharomyces cerevisiae, whereas the most abundant mitochondrial phospholipid, phosphatidylcholine (PC), is largely dispensable. Surprisingly, choline (Cho), which is a biosynthetic precursor of PC, has been shown to rescue the respiratory growth of mitochondrial PE-deficient yeast; however, the mechanism underlying this rescue has remained unknown. Using a combination of yeast genetics, lipid biochemistry, and cell biological approaches, we uncover the mechanism by showing that Cho rescues mitochondrial respiration by partially replenishing mitochondrial PE levels in yeast cells lacking the mitochondrial PE-biosynthetic enzyme Psd1. This rescue is dependent on the conversion of Cho to PC via the Kennedy pathway as well as on Psd2, an enzyme catalyzing PE biosynthesis in the endosome. Metabolic labeling experiments reveal that in the absence of exogenously supplied Cho, PE biosynthesized via Psd2 is mostly directed to the methylation pathway for PC biosynthesis and is unavailable for replenishing mitochondrial PE in Psd1-deleted cells. In this setting, stimulating the Kennedy pathway for PC biosynthesis by Cho spares Psd2-synthesized PE from the methylation pathway and redirects it to the mitochondria. Cho-mediated elevation in mitochondrial PE is dependent on Vps39, which has been recently implicated in PE trafficking to the mitochondria. Accordingly, epistasis experiments placed Vps39 downstream of Psd2 in Cho-based rescue. Our work, thus, provides a mechanism of Cho-based rescue of mitochondrial PE deficiency and uncovers an intricate interorganelle phospholipid regulatory network that maintains mitochondrial PE homeostasis.

Recombination and Pol ζ Rescue Defective DNA Replication upon Impaired CMG Helicase-Pol ε Interaction.

The CMG complex (Cdc45, Mcm2–7, GINS (Psf1, 2, 3, and Sld5)) is crucial for both DNA replication initiation and fork progression. The CMG helicase interaction with the leading strand DNA polymerase epsilon (Pol ε) is essential for the preferential loading of Pol ε onto the leading strand, the stimulation of the polymerase, and the modulation of helicase activity. Here, we analyze the consequences of impaired interaction between Pol ε and GINS in Saccharomyces cerevisiae cells with the psf1-100 mutation. This significantly affects DNA replication activity measured in vitro, while in vivo, the psf1-100 mutation reduces replication fidelity by increasing slippage of Pol ε, which manifests as an elevated number of frameshifts. It also increases the occurrence of single-stranded DNA (ssDNA) gaps and the demand for homologous recombination. The psf1-100 mutant shows elevated recombination rates and synthetic lethality with rad52Δ. Additionally, we observe increased participation of DNA polymerase zeta (Pol ζ) in DNA synthesis. We conclude that the impaired interaction between GINS and Pol ε requires enhanced involvement of error-prone Pol ζ, and increased participation of recombination as a rescue mechanism for recovery of impaired replication forks.

B3galt6 Knock-Out Zebrafish Recapitulate β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region.

Proteoglycans are structurally and functionally diverse biomacromolecules found abundantly on cell membranes and in the extracellular matrix. They consist of a core protein linked to glycosaminoglycan chains via a tetrasaccharide linkage region. Here, we show that CRISPR/Cas9-mediated b3galt6 knock-out zebrafish, lacking galactosyltransferase II, which adds the third sugar in the linkage region, largely recapitulate the phenotypic abnormalities seen in human β3GalT6-deficiency disorders. These comprise craniofacial dysmorphism, generalized skeletal dysplasia, skin involvement and indications for muscle hypotonia. In-depth TEM analysis revealed disturbed collagen fibril organization as the most consistent ultrastructural characteristic throughout different affected tissues. Strikingly, despite a strong reduction in glycosaminoglycan content, as demonstrated by anion-exchange HPLC, subsequent LC-MS/MS analysis revealed a small amount of proteoglycans containing a unique linkage region consisting of only three sugars. This implies that formation of glycosaminoglycans with an immature linkage region is possible in a pathogenic context. Our study, therefore unveils a novel rescue mechanism for proteoglycan production in the absence of galactosyltransferase II, hereby opening new avenues for therapeutic intervention.

PKC downregulation upon rapamycin treatment attenuates mitochondrial disease.

Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. mTOR inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 KO mouse); however, the mechanism of rescue is unknown. Here we identify PKC downregulation as a key event mediating the beneficial effects of rapamycin treatment of Ndufs4 KO mice. Assessing the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice we find that rapamycin restores mitochondrial protein levels, inhibits signaling through both mTOR complexes, and reduces the abundance and activity of multiple protein kinase C (PKC) isoforms. Administration of PKC inhibitors increases survival, delays neurological deficits, prevents hair loss, and decreases inflammation in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.Reporting SummaryFurther information on research design is available in the Nature Research Reporting Summary linked to this article.

TRF2 Mediates Replication Initiation within Human Telomeres to Prevent Telomere Dysfunction

SUMMARYThe telomeric shelterin protein telomeric repeat-binding factor 2 (TRF2) recruits origin recognition complex (ORC) proteins, the foundational building blocks of DNA replication origins, to telomeres. We seek to determine whether TRF2-recruited ORC proteins give rise to functional origins in telomere repeat tracts. We find that reduction of telomeric recruitment of ORC2 by expression of an ORC interaction-defective TRF2 mutant significantly reduces telomeric initiation events in human cells. This reduction in initiation events is accompanied by telomere repeat loss, telomere aberrations and dysfunction. We demonstrate that telomeric origins are activated by induced replication stress to provide a key rescue mechanism for completing compromised telomere replication. Importantly, our studies also indicate that the chromatin remodeler SNF2H promotes telomeric initiation events by providing access for ORC2. Collectively, our findings reveal that active recruitment of ORC by TRF2 leads to formation of functional origins, providing an important mechanism for avoiding telomere dysfunction and rescuing challenged telomere replication.

Dsg2 Upregulation as a Rescue Mechanism in Pemphigus.

In pemphigus vulgaris (PV), autoantibodies directed against the desmosomal cadherin desmoglein (Dsg) 3 cause loss of intercellular adhesion. It is known that Dsg3 interactions are directly inhibited by autoantibody binding and that Dsg2 is upregulated in epidermis of PV patients. Here, we investigated whether heterophilic Dsg2-Dsg3 interactions occur and would modulate PV pathogenesis. Dsg2 was upregulated in PV patients’ biopsies and in a human ex vivo pemphigus skin model. Immunoprecipitation and cell-free atomic force microscopy (AFM) experiments demonstrated heterophilic Dsg2-Dsg3 interactions. Similarly, in Dsg3-deficient keratinocytes with severely disturbed intercellular adhesion Dsg2 was upregulated in the desmosome containing fraction. AFM revealed that Dsg2-Dsg3 heterophilic interactions showed binding frequency, strength, Ca2+-dependency and catch-bond behavior comparable to homophilic Dsg3-Dsg3 or homophilic Dsg2-Dsg2 interactions. However, heterophilic Dsg2-Dsg3 interactions had a longer lifetime compared to homophilic Dsg2-Dsg2 interactions and PV autoantibody-induced direct inhibition was significantly less pronounced for heterophilic Dsg2-Dsg3 interactions compared to homophilic Dsg3 interactions. In contrast, a monoclonal anti-Dsg2 inhibitory antibody reduced heterophilic Dsg2-Dsg3 and homophilic Dsg2-Dsg2 binding to the same degree and further impaired intercellular adhesion in Dsg3-deficient keratinocytes. Taken together, the data demonstrate that Dsg2 undergoes heterophilic interactions with Dsg3, which may attenuate autoantibody-induced loss of keratinocyte adhesion in pemphigus.