Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates
| العنوان: | Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates |
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| المؤلفون: | Junghyun Lim, Rong Wang, Masaaki Komatsu, Shuai Wu, M. Lenard Lachenmayer, Young J. Oh, Wenchao Liu, Yanxiang Zhao, Zhenyu Yue, Mondira Kundu |
| المصدر: | PLoS Genetics Lim, Junghyun; Lachenmayer, Lenard; Wu, Shuai; Liu, Wenchao; Kundu, Mondira; Wang, Rong; Komatsu, Masaaki; Oh, Young J; Zhao, Yanxiang; Yue, Zhenyu (2015). Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS genetics, 11(2), e1004987. Public Library of Science 10.1371/journal.pgen.1004987 <http://dx.doi.org/10.1371/journal.pgen.1004987Test> PLoS Genetics, Vol 11, Iss 2, p e1004987 (2015) |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Sequestosome-1 Protein, Cancer Research, lcsh:QH426-470, 610 Medicine & health, Nerve Tissue Proteins, Biology, Protein Serine-Threonine Kinases, BAG3, 03 medical and health sciences, Protein Aggregates, 0302 clinical medicine, Phagosomes, Genetics, Autophagy, Autophagy-Related Protein-1 Homolog, Humans, Phosphorylation, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Adaptor Proteins, Signal Transducing, 0303 health sciences, Huntingtin Protein, Ubiquitin, Intracellular Signaling Peptides and Proteins, Signal transducing adaptor protein, Autophagy-related protein 13, Ubiquitinated Proteins, 3. Good health, Cell biology, lcsh:Genetics, Proteostasis, Huntington Disease, Peptides, 030217 neurology & neurosurgery, Protein Binding, Research Article |
| الوصف: | Disruption of proteostasis, or protein homeostasis, is often associated with aberrant accumulation of misfolded proteins or protein aggregates. Autophagy offers protection to cells by removing toxic protein aggregates and injured organelles in response to proteotoxic stress. However, the exact mechanism whereby autophagy recognizes and degrades misfolded or aggregated proteins has yet to be elucidated. Mounting evidence demonstrates the selectivity of autophagy, which is mediated through autophagy receptor proteins (e.g. p62/SQSTM1) linking autophagy cargos and autophagosomes. Here we report that proteotoxic stress imposed by the proteasome inhibition or expression of polyglutamine expanded huntingtin (polyQ-Htt) induces p62 phosphorylation at its ubiquitin-association (UBA) domain that regulates its binding to ubiquitinated proteins. We find that autophagy-related kinase ULK1 phosphorylates p62 at a novel phosphorylation site S409 in UBA domain. Interestingly, phosphorylation of p62 by ULK1 does not occur upon nutrient starvation, in spite of its role in canonical autophagy signaling. ULK1 also phosphorylates S405, while S409 phosphorylation critically regulates S405 phosphorylation. We find that S409 phosphorylation destabilizes the UBA dimer interface, and increases binding affinity of p62 to ubiquitin. Furthermore, lack of S409 phosphorylation causes accumulation of p62, aberrant localization of autophagy proteins and inhibition of the clearance of ubiquitinated proteins or polyQ-Htt. Therefore, our data provide mechanistic insights into the regulation of selective autophagy by ULK1 and p62 upon proteotoxic stress. Our study suggests a potential novel drug target in developing autophagy-based therapeutics for the treatment of proteinopathies including Huntington’s disease. Author Summary Accumulation of misfolded proteins deposited in the form of inclusion bodies is a common pathological hallmark for many human genetic diseases, particularly for the neurodegenerative disorders. The aggregation of the disease related proteins suggests a failure of the cellular machineries that maintain the protein homeostasis or proteostasis. The cellular clearance pathways, e.g. autophagy-lysosomal pathway, may not be of high efficiency in the face of rapid formation of misfolded protein aggregates. Thus, understanding of intrinsic mechanism whereby autophagy offers protection to cells by removing toxic protein aggregates is important. Here we report that a signaling transduction event that chemically modifies autophagy receptor protein p62/SQSTM1 regulates the receptor’s binding affinity to small molecule called ubiquitin(essential for marking the protein for degradation), as well as the selective degradation of targeted proteins. Furthermore, we find that expression of Huntington’s disease (HD) associated protein aggregates (containing polyglutamine or polyQ expansion) triggers the same modification of p62, which is dependent on the length of the polyQ expansion, suggesting a protective response of the cell by activating autophagy toward degradation of toxic aggregates. The modification of p62 also occurs in HD model brains in an age-dependent manner. Our study sheds light on the regulation of selective autophagy and provides a rationale for targeting p62 modification to treat aggregate diseases including HD. |
| وصف الملف: | application/pdf |
| تدمد: | 1553-7404 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::026e3c896a58ffc2e02da0cc3a1b49a9Test https://pubmed.ncbi.nlm.nih.gov/25723488Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....026e3c896a58ffc2e02da0cc3a1b49a9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537404 |
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