Abstract
Aggresome-like induced structures (ALIS) have been described as ubiquitinated protein-containing aggresomes transiently formed in response to various stresses. In this study, we provide evidence that ALIS composed of SQSTM1/p62 act as a key determinant of oxidative stress-induced parthanatos, which is newly discovered and distinct from regular programmed cell death. Interestingly, we first found that chemical stresses induced by particular chemical drugs, such as several cephalosporin antibiotics, cause oxidative stress-mediated parthanatos, accompanied by the ALIS formation. Blocking the ALIS formation potently suppressed the parthanatos, and p62 knockout cells exhibited the attenuated ALIS formation and high resistance to parthanatos. Moreover, we also found that the redox-sensing activity of p62 is required for nuclear accumulation of the p62-based ALIS, resulting in the induction of parthanatos. Together, our results demonstrate unexpected functions of p62 and ALIS as cell death mediators sensing oxidative stress, and thus uncover a novel mechanism whereby p62 mediates parthanatos.
Highlights
Aggresome-like induced structures (ALIS) refer to ubiquitin-containing aggresomes that function as protein storage compartments for the sequestration of misfolded proteins, which are generated by various cellular stresses[1]
ALIS are conceived as stressinduced protein storage compartments for substrates of the proteasome and autophagy, our results indicate that the p62-based ALIS serve as microdomains sensing oxidative stress and have important roles in signaling epicenters and mediators of oxidative stress-induced parthanatos
We found that several cephalosporin antibiotics exhibit cytotoxicity in mammalian cells, even though they are conceived as safe drugs and are commonly prescribed
Summary
ALIS refer to ubiquitin-containing aggresomes that function as protein storage compartments for the sequestration of misfolded proteins, which are generated by various cellular stresses[1]. Noguchi et al Cell Death and Disease (2018)9:1193 diseases, p62 is found in inclusion bodies containing polyubiquitinated protein aggregates, such as Lewy bodies in Parkinson disease, Huntingtin aggregates in Huntington disease, and neurofibrillary tangles in Alzheimer disease[13,14,15,16]. In liver diseases, such as alcoholic and nonalcoholic steatohepatitis, Mallory body in hepatocytes includes large amounts of p6216. These findings indicate a pathologically close link between p62 and the diseases associated with protein aggregates, including ALIS
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