Proteotoxic Stress Induces Phosphorylation of p62/SQSTM1 by ULK1 to Regulate Selective Autophagic Clearance of Protein Aggregates

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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.

Vyšlo v časopise: Proteotoxic Stress Induces Phosphorylation of p62/SQSTM1 by ULK1 to Regulate Selective Autophagic Clearance of Protein Aggregates. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004987
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004987

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