Regulation Of Protein Degradation Research Articles

Investigating a novel role of LARP along the algal TOR pathway

Over the last few decades, global warming has become an increasingly desperate rallying cry for the need to find and optimize efficient renewable energy sources.1 Microalgae are considered apromising source of energy because they contain a high concentration of lipids, but due to inefficiencies in their lipid production, microalgae cannot produce enough biofuel to replace current fuel needs.2Chlamydomonas reinhardtiiis a unicellular green alga that is a great candidate for manipulation and an excellent model organism used to better understand algal metabolic pathways and improve biofuels. Our previous research has shown that inhibiting the target of rapamycin (TOR) kinase of C. reinhardtii with AZD8055 causes the growth of the cell cultures to stagnate, the photosynthetic efficiency to decrease, as well as a direct link between oxidative signaling and the upregulation of TAGs.3 Additionally, our work has indicated that La‐related protein 1 (LARP1) is a TOR target and involved in propagating the intracellular response following inhibition. In mammalian systems, LARP1 interacts directly with mTOR and regulates protein synthesis by binding and stabilizing mRNA before recruiting polysomes to initiate translation. LARP1 is essential in mammalian systems, and deficiencies lead to inhibited growth, defects, and increased apoptosis. However, LARP1 deficiency in C. reinhardtii does not cause the same phenotype, indicating a distinct uncharacterized role in phototrophic organisms.This study seeks to understand this role by using a LARP1 knockout mutant to compare the physiological changes following inhibition with the parent strain. Both strains were assessed for biochemical composition, cell size, and photosynthetic electron fluxes. Together, these data support LARP1 as a regulator of protein degradation along the TOR pathway. The differential delineation of metabolic processes in LARP1 knockouts provides a framework for further TOR pathway characterization in phototrophic eukaryotes.Literature References1 IPCC, 2014: Climate Change 2014: Synthesis Report. Contribution of Working Groups I, II and III to the Fifth Assessment Report of the Intergovernmental Panel on Climate Change [Core Writing Team, R.K. Pachauri and L.A. Meyer (eds.)]. IPCC, Geneva, Switzerland, 151 pp.2 Sharma, Kalpesh K., Holger Schuhmann, and Peer M. Schenk.. High Lipid Induction in Microalgae for Biodiesel Production. 2012. Energies. 5:1532‐1553.3 Ford, M. M., Smythers, A. L., McConnell, E. W., Lowery, S. C., Kolling, D. R. J., & Hicks, L. M. (2019). Inhibition of TOR in Chlamydomonas reinhardtii leads to rapid cysteine oxidation reflecting sustained physiological changes. Cells, 8(10), 1171.

OTUB1: A Key Player in the Adaptive Cardiac Hypertrophy

Deubiquitinases (DUBs), a family enzymes that reverse the process of ubiquitination, participate in diverse cellular processes through regulating protein degradation, intracellular trafficking, cell signaling, and protein‐protein interaction. The functional importance of DUBs in cardiac pathophysiology remains poorly defined. Herein, we report a critical role of OTUB1, one of the most highly expressed DUBs in the heart, in adaptive cardiac remodeling. Analysis of RNA sequencing data revealed that OTUB1 is upregulated in the failing human hearts. OTUB1 is also upregulated and activated in cardiomyocytes (CMs) treated with adrenergic agonists. OTUB1‐deficient CMs were resistant to phenylephrine (PE) ‐ and isoproterenol‐induced CM hypertrophy as characterized by attenuated cell enlargement, decreased fetal gene activation, and diminished protein synthesis. In vivo, CM‐specific deletion of OTUB1 in the developing mouse heart caused dilated cardiomyopathy without a prior development of compensatory cardiac hypertrophy, eventually leading to heart failure and premature lethality of mice by 6 months of age. The severe cardiac phenotype is accompanied by lipid accumulation, ER dilatation, prevalent autophagic vesicles containing ribosomes, as well as dysregulated expression of metabolic and ribosome genes. Delivery of wild‐type OTUB1, but not the enzymatic dead mutant, via AAV9 to OTUB1‐deficient hearts attenuated cardiac dysfunction and prolonged the lifespan of mice. On the molecular level, OTUB1 deficiency blunted mTOR signaling in cultured CMs and mouse hearts. Our findings indicate that OTUB1 is indispensable for the development of adaptive cardiac hypertrophy, possibly through modulating mTOR signaling.

Valosin-containing protein regulates the stability of fused in sarcoma granules in cells by changing ATP concentrations.

Fused in sarcoma (FUS), a DNA/RNA-binding protein, undergoes liquid-liquid phase separation to form granules in cells. Aberrant FUS granulation is associated with neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We found that FUS granules contain a multifunctional AAA ATPase, valosin-containing protein (VCP), which is known as a key regulator of protein degradation. FUS granule stability depends on ATP concentrations in cells. VCP ATPase changes the FUS granule stability time-dependently by consuming ATP to reduce its concentrations in the granules: VCPs in de novo FUS granules stabilize the granules, while long-lasting VCP colocalization destabilizes the granules. The proteolysis-promoting function of VCP may subsequently dissolve the unstabilized granules. We propose that VCP colocalized to the FUS granules acts as a timer to limit the residence time of the granules in cells.

A cryptic K48 ubiquitin chain binding site on UCH37 is required for its role in proteasomal degradation.

Degradation by the 26 S proteasome is an intricately regulated process fine tuned by the precise nature of ubiquitin modifications attached to a protein substrate. By debranching ubiquitin chains composed of K48 linkages, the proteasome-associated ubiquitin C-terminal hydrolase UCHL5/UCH37 serves as a positive regulator of protein degradation. How UCH37 achieves specificity for K48 chains is unclear. Here, we use a combination of hydrogen-deuterium mass spectrometry, chemical crosslinking, small-angle X-ray scattering, nuclear magnetic resonance (NMR), molecular docking, and targeted mutagenesis to uncover a cryptic K48 ubiquitin (Ub) chain-specific binding site on the opposite face of UCH37 relative to the canonical S1 (cS1) ubiquitin-binding site. Biochemical assays demonstrate the K48 chain-specific binding site is required for chain debranching and proteasome-mediated degradation of proteins modified with branched chains. Using quantitative proteomics, translation shutoff experiments, and linkage-specific affinity tools, we then identify specific proteins whose degradation depends on the debranching activity of UCH37. Our findings suggest that UCH37 and potentially other DUBs could use more than one S1 site to perform different biochemical functions.

Ubiquitin-Proteasome System-Regulated Protein Degradation in Spermatogenesis.

Spermatogenesis is a prolonged and highly ordered physiological process that produces haploid male germ cells through more than 40 steps and experiences dramatic morphological and cellular transformations. The ubiquitin proteasome system (UPS) plays central roles in the precise control of protein homeostasis to ensure the effectiveness of certain protein groups at a given stage and the inactivation of them after this stage. Many UPS components have been demonstrated to regulate the progression of spermatogenesis at different levels. Especially in recent years, novel testis-specific proteasome isoforms have been identified to be essential and unique for spermatogenesis. In this review, we set out to discuss our current knowledge in functions of diverse USP components in mammalian spermatogenesis through: (1) the composition of proteasome isoforms at each stage of spermatogenesis; (2) the specificity of each proteasome isoform and the associated degradation events; (3) the E3 ubiquitin ligases mediating protein ubiquitination in male germ cells; and (4) the deubiquitinases involved in spermatogenesis and male fertility. Exploring the functions of UPS machineries in spermatogenesis provides a global picture of the proteome dynamics during male germ cell production and shed light on the etiology and pathogenesis of human male infertility.

Time-resolved single-cell sequencing identifies multiple waves of mRNA decay during the mitosis-to-G1 phase transition.

Accurate control of the cell cycle is critical for development and tissue homeostasis, and requires precisely timed expression of many genes. Cell cycle gene expression is regulated through transcriptional and translational control, as well as through regulated protein degradation. Here, we show that widespread and temporally controlled mRNA decay acts as an additional mechanism for gene expression regulation during the cell cycle in human cells. We find that two waves of mRNA decay occur sequentially during the mitosis-to-G1 phase transition, and we identify the deadenylase CNOT1 as a factor that contributes to mRNA decay during this cell cycle transition. Collectively, our data show that, akin to protein degradation, scheduled mRNA decay helps to reshape cell cycle gene expression as cells move from mitosis into G1 phase.

USP14: Structure, Function, and Target Inhibition.

Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme (DUB), is associated with proteasomes and exerts a dual function in regulating protein degradation. USP14 protects protein substrates from degradation by removing ubiquitin chains from proteasome-bound substrates, whereas promotes protein degradation by activating the proteasome. Increasing evidence have shown that USP14 is involved in several canonical signaling pathways, correlating with cancer, neurodegenerative diseases, autophagy, immune responses, and viral infections. The activity of USP14 is tightly regulated to ensure its function in various cellular processes. Structural studies have demonstrated that free USP14 exists in an autoinhibited state with two surface loops, BL1 and BL2, partially hovering above and blocking the active site cleft binding to the C-terminus of ubiquitin. Hence, both proteasome-bound and phosphorylated forms of USP14 require the induction of conformational changes in the BL2 loop to activate its deubiquitinating function. Due to its intriguing roles in the stabilization of disease-causing proteins and oncology targets, USP14 has garnered widespread interest as a therapeutic target. In recent years, significant progress has been made on identifying inhibitors targeting USP14, despite the complexity and challenges in improving their selectivity and affinity for USP14. In particular, the crystal structures of USP14 complexed with IU1-series inhibitors revealed the underlying allosteric regulatory mechanism and enabled the further design of potent inhibitors. In this review, we summarize the current knowledge regarding the structure, regulation, pathophysiological function, and selective inhibition of USP14, including disease associations and inhibitor development.

Site-Specific Proteasome Inhibitors.

Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases.

Quantitative systems pharmacology model of amyloid and tau to explore efficacy of therapy targeting modified forms of amyloid

AbstractBackgroundAmyloid targeting therapy in different variations is still under development. One of the potential targets is modified forms of amyloid, Ab3p. They are very specific marker found in plaques of AD subjects, and demonstrate higher toxicity to neurons. Its correlation with tau load and AD severity is stronger than for non‐modified forms. Specific therapy targeting modified Ab may be more effective and less toxic due to lower required concentration of antibodies. Glutaminyl cyclase (QC) inhibitors have considerable BBB penetration and concomitant anti‐inflammatory activities. Monoclonal antibodies to specific to pGlu3‐Ab successfully reduce cognitive impairment in preclinical settings. Quantitative systems pharmacology QSP model is a good tool to study contribution of protein modification to disease progression and investigating sensitivity of overall system to specific targeting.MethodQSP model was developed to describing amyloid production and distribution, hetero‐oligomerization of Ab1‐40, Ab1‐42 and pGlu3‐Ab. It has been combined with description of tau pathology and neuron homeostasis (NH) model. NH model describes processes regulating protein degradation and transport. Modified amyloid polymerizes with higher rate and resistant to degradation. Rate of amyloid modification was assumed to be one of the drivers, depending on age (we assumed it can be related to the calcium EPR stress in neurons and microglia activation due to inflammatory stimuli). Amyloid and tau during accumulation disrupt transport, proteasomal and autolysosome system. The model was calibrated on multiple in vitro and in vivo data, as well as preclinical and clinical data for treatments by immunotherapies.ResultIntegrated model describes accumulation of amyloid and tau according to Braak stages. It captures the role of intraneuronal processes on tau and amyloid metabolism. Model describes influence of amyloid modification on total accumulation of amyloid. Both QC inhibition and targeting by antibodies attenuate accumulation of amyloid in brain. Tau pathology progression is reduced, assuming that binding of antibody prevents toxicity of pGlu3‐Ab on tau kinase activation and calcium influx.ConclusionModel can be used to analyze contribution of different amyloid forms to pathology and efficacy of specific therapies on multiple biomarkers. It can be used for explorations of different combinations and regimens.

Deubiquitinase USP13 promotes the epithelial-mesenchymal transition and metastasis in gastric cancer by maintaining Snail protein

The dynamic balance between ubiquitination and deubiquitination is a key mechanism that regulates protein degradation and maintains cell protein homeostasis. Ubiquitin-specific peptidase 13 (USP13), a deubiquitinase (DUB), regulates various physiological and pathological processes, including cancer. A previous study reported that high USP13 mRNA expression confers poor prognosis in gastric cancer (GC). However, the biological function of USP13 in GC remains unknown. Here, we revealed that USP13 expression was upregulated in GC tissue samples compared to noncancerous tissues. USP13-positive expression was associated with poor differentiation, high invasiveness, and advanced tumor stage. Notably, upregulated USP13 expression was closely correlated with the reduced survival of GC patients. We also confirmed increased USP13 expression in GC cell lines. USP13 knockdown prominently suppressed MGC-803 cell migration and invasion. Conversely, USP13 overexpression markedly enhanced SGC-7901 cell motility. Furthermore, USP13 positively regulates the epithelial-mesenchymal transition (EMT) of GC cells. Interestingly, USP13 remarkably enhanced Snail protein expression but did not affect its mRNA levels in GC cells. We confirmed a positive correlation between USP13 and Snail expression in GC tissues. Mechanistically, USP13 knockdown promoted Snail degradation, which could be blocked by the proteasome inhibitor MG132. USP13 interacted with Snail to deubiquitinate and stabilize Snail in GC cells. Finally, Snail knockdown significantly blocked USP13-induced SGC-7901 cell migration and invasion. In conclusion, USP13 overexpression was frequently detected in GC and contributed to the EMT and metastasis of GC by stabilizing Snail.

On the Role of the Immunoproteasome in Protein Homeostasis.

Numerous cellular processes are controlled by the proteasome, a multicatalytic protease in the cytosol and nucleus of all eukaryotic cells, through regulated protein degradation. The immunoproteasome is a special type of proteasome which is inducible under inflammatory conditions and constitutively expressed in hematopoietic cells. MECL-1 (β2i), LMP2 (β1i), and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome (IP), which is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Furthermore, the immunoproteasome is involved in T cell expansion and inflammatory diseases. In recent years, targeting the immunoproteasome in cancer, autoimmune diseases, and transplantation proved to be therapeutically effective in preclinical animal models. However, the prime function of standard proteasomes and immunoproteasomes is the control of protein homeostasis in cells. To maintain protein homeostasis in cells, proteasomes remove proteins which are not properly folded, which are damaged by stress conditions such as reactive oxygen species formation, or which have to be degraded on the basis of regular protein turnover. In this review we summarize the latest insights on how the immunoproteasome influences protein homeostasis.

FSH inhibits autophagy and lysosomal biogenesis to regulate protein degradation in cultured goat Sertoli cells

Although the follicle-stimulating hormone (FSH) plays a vital role in male reproduction, the molecular relationships among FSH, autophagy, and the secretory function of Sertoli cells remain largely undetermined. In this study, we sought to investigate the effects of FSH on dairy goat Sertoli cell autophagy and the role of autophagy in protein clearance. FSH treatment of primary Sertoli cells was found to enhance the expression level of LC3-II, reduce p62 degradation and the number of lysosomes, and downregulate the levels of LAMP2 protein and lysosomal gene mRNAs. Further analyses revealed that starvation-induced autophagy promotes the translocation of transcription factor EB (TFEB) from the cytoplasm to nucleus and its binding to the promoter region of LAMP2, whereas FSH suppresses the nuclear translocation of TFEB. Moreover, we found that the FSH-mediated inhibition of autophagy extends the biological half-lives of androgen-binding protein (ABP), glial-derived neurotrophic factor (GDNF), and stem cell factor (SCF) and promotes the secretion of these proteins. Collectively, these observations indicate that FSH inhibits autophagy by reducing lysosomal biogenesis, which is associated with the suppression of TFEB nuclear translocation via activation of the PI3K/Akt/mTOR pathway, thereby extending the biological half-lives and enhancing the expression of ABP, GDNF, and SCF in dairy goat Sertoli cells.

Autophagy Regulation by Crosstalk between miRNAs and Ubiquitination System.

MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes with ~22 nucleotides which are involved in the regulation of post-transcriptional gene expression. Ubiquitination and deubiquitination are common post-translational modifications in eukaryotic cells and important pathways in regulating protein degradation and signal transduction, in which E3 ubiquitin ligases and deubiquitinases (DUBs) play a decisive role. MiRNA and ubiquitination are involved in the regulation of most biological processes, including autophagy. Furthermore, in recent years, the direct interaction between miRNA and E3 ubiquitin ligases or deubiquitinases has attracted much attention, and the cross-talk between miRNA and ubiquitination system has been proved to play key regulatory roles in a variety of diseases. In this review, we summarized the advances in autophagy regulation by crosstalk between miRNA and E3 ubiquitin ligases or deubiquitinases.

Neddylation and anti-tumor immunity.

Contrary to chemotherapy, novel targeted therapies are associated with diverse immunomodulatory effects. Nedd8 is a small ubiquitin-like modifier that is involved in regulation of protein degradation. Neddylation is a promising target in cancer. Pevonedistat, a small molecule inhibitor of the Nedd8-activating enzyme, demonstrates pre-clinical activity in multiple tumor types. Recent studies have revealed that neddylation is important in immunity. We and others have shown that interfering with neddylation causes downstream immunomodulatory effects potentially leading to enhanced anti-tumor immunity. Thus, Nedd8 is a promising target in immuno-oncology.

RFWD2 Knockdown as a Blocker to Reverse the Oncogenic Role of TRIB2 in Lung Adenocarcinoma.

RFWD2, an E3 ubiquitin ligase, is overexpressed in numerous human cancers, including leukemia, lung cancer, breast cancer, renal cell carcinoma, and colorectal cancer. The roles of RFWD2 in cancer are related to the targeting of its substrates for ubiquitination and degradation. This study aimed to investigate the role of TRIB2 in relation to the regulation of protein degradation through RFWD2. inBio Discover™ results demonstrated that TRIB2 can perform its functions by interacting with RFWD2 or other factors. TRIB2 can interact with and regulate RFWD2, which further attends the proteasome-mediated degradation of the RFWD2 substrate p-IκB-α. TRIB2 colocalizes with RFWD2-related IκB-α to form a ternary complex and further affects the IκB-α degradation by regulating its phosphorylation. Specific domain analysis showed that TRIB2 may bind to RFWD2 via its C-terminus, whereas it binds to IκB via its pseudokinase domain. TRIB2 acts as an oncogene and promotes cancer cell proliferation and migration, whereas RFWD2 knockdown reversed the role of TRIB2 in promoting cancer cell growth and colony formation in vitro and in vivo. In summary, this study reveals that TRIB2 promotes the progression of cancer by affecting the proteasome-mediated degradation of proteins through the interaction with RFWD2.

ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy

The evolutionarily conserved ULK1 kinase complex acts as gatekeeper of canonical autophagy and regulates induction of autophagosome biogenesis. To better understand control of ULK1 and analyze whether ULK1 has broader functions that are also linked to the later steps of autophagy, we perform comprehensive phosphoproteomic analyses. Combining invivo with invitro data, we identify numerous direct ULK1 target sites within autophagy-relevant proteins that are critical for autophagosome maturation and turnover. In addition, we highlight an intimate crosstalk between ULK1 and several phosphatase complexes. ULK1 is not only a PP2A target but also directly phosphorylates the regulatory PP2A subunit striatin, activating PP2A and serving as positive feedback to promote autophagy-dependent protein turnover. Thus, ULK1 and phosphatase activities are tightly coordinated to robustly regulate protein degradation by autophagy.

USP39 promotes tumorigenesis by stabilizing and deubiquitinating SP1 protein in hepatocellular carcinoma

Deubiquitinating enzyme (DUB) can hydrolyze ubiquitin molecules from the protein bound with ubiquitin, and reversely regulate protein degradation. The ubiquitin-specific proteases (USP) family are cysteine proteases, which owns the largest members and diverse structure among the currently known DUB. The important roles of ubiquitin-specific peptidase39 (USP39) in cancer have been widely investigated. However, little is known about the putative de-ubiquitination function of USP39 in hepatocellular carcinoma (HCC) and the mechanisms of USP39 regulating tumor growth. Here, we used bioinformatics methods to reveal that USP39 expression is significantly upregulated in several cancer database. High expression of USP39 is correlated with poor prognosis of HCC patients. Then, we identify the specificity protein 1 (SP1), as a novel subtract of the USP39. We observe that USP39 stabilizes SP1 protein and prolongs its half-life by promoting its deubiquitylation pathway. In addition, our results show USP39 promotes cell proliferation by SP1-depenet manner in vivo and vitro. Knocking-down of USP39 promotes the cell apoptosis and arrest of the cell cycle, whereas SP1 forcefully reversed these effects. Taken together, our results suggest that USP39 participates the deubiquitylation of SP1 protein, providing new pathway for understand the upstream signaling for oncogene SP1.

USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

BackgroundHepatocellular carcinoma (HCC) remains a medical challenge due to its high proliferation and metastasis. Although deubiquitinating enzymes (DUBs) play a key role in regulating protein degradation, their pathological roles in HCC have not been fully elucidated.MethodsBy using biomass spectrometry, co-immunoprecipitation, western blotting and immunofluorescence assays, we identify ribosomal protein S16 (RPS16) as a key substrate of ubiquitin-specific peptidase 1 (USP1). The role of USP1-RPS16 axis in the progression of HCC was evaluated in cell cultures, in xenograft mouse models, and in clinical observations.ResultsWe show that USP1 interacts with RPS16. The depletion of USP1 increases the level of K48-linked ubiquitinated-RPS16, leading to proteasome-dependent RPS16 degradation. In contrast, overexpression of USP1-WT instead of USP1-C90A (DUB inactivation mutant) reduces the level of K48-linked ubiquitinated RPS16, thereby stabilizing RPS16. Consequently, USP1 depletion mimics RPS16 deficiency with respect to the inhibition of growth and metastasis, whereas transfection-enforced re-expression of RPS16 restores oncogenic-like activity in USP1-deficient HCC cells. Importantly, the high expression of USP1 and RPS16 in liver tissue is a prognostic factor for poor survival of HCC patients.ConclusionsThese findings reveal a previously unrecognized role for the activation of USP1-RPS16 pathway in driving HCC, which may be further developed as a novel strategy for cancer treatment.

HOTAIR beyond repression: In protein degradation, inflammation, DNA damage response, and cell signaling

Long noncoding RNAs (lncRNAs) are pervasively transcribed from the mammalian genome as transcripts that are usually >200 nucleotides long. LncRNAs generally do not encode proteins but are involved in a variety of physiological processes, principally as epigenetic regulators. HOX transcript antisense intergenic RNA (HOTAIR) is a well-characterized lncRNA that has been implicated in several cancers and in various other diseases. HOTAIR is a repressor lncRNA and regulates various repressive chromatin modifications. However, recent studies have revealed additional functions of HOTAIR in regulation of protein degradation, microRNA (miRNA) sponging, NF-κB activation, inflammation, immune signaling, and DNA damage response. Herein, we have summarized the diverse functions and modes of action of HOTAIR in protein degradation, inflammation, DNA repair, and diseases, beyond its established functions in gene silencing.

Inositol pyrophosphates promote MYC polyubiquitination by FBW7 to regulate cell survival.

The transcription factor MYC regulates cell survival and growth, and its level is tightly controlled in normal cells. We report that serine pyrophosphorylation - a posttranslational modification triggered by inositol pyrophosphate signaling molecules - controls MYC levels via regulated protein degradation. We find that endogenous MYC is stabilized and less polyubiquitinated in cells with reduced inositol pyrophosphates. We show that the inositol pyrophosphate 5-IP7 transfers its high-energy beta phosphate moiety to pre-phosphorylated serine residues in the central PEST domain of MYC. Loss of serine pyrophosphorylation in the PEST domain lowers the extent of MYC polyubiquitination and increases its stability. Fusion to the MYC PEST domain lowers the stability of GFP, but this effect is dependent on the extent of PEST domain pyrophosphorylation. The E3 ubiquitin ligase FBW7 can bind directly to the PEST domain of MYC, and this interaction is exclusively dependent on serine pyrophosphorylation. A stabilized, pyrophosphorylation-deficient form of MYC increases cell death during growth stress in untransformed cells. Splenocytes from mice lacking IP6K1, a kinase responsible for the synthesis of 5-IP7, have higher levels of MYC, and show increased cell proliferation in response to mitogens, compared with splenocytes from wild type mice. Thus, control of MYC stability through a novel pyro-phosphodegron provides unexpected insight into the regulation of cell survival in response to environmental cues.