Reactive sulfur species disaggregate the SQSTM1/p62-based aggresome-like induced structures via the HSP70 induction and prevent parthanatos

Reactive sulfur species (RSS) have emerged as key regulators of protein quality control. However, the mechanisms by which RSS contribute to cellular processes are not fully understood. In this study, we identified a novel function of RSS in preventing parthanatos, a non-apoptotic form of cell death that is induced by poly (ADP-ribose) polymerase-1 (PARP-1) and mediated by the aggresome-like induced structures (ALIS) composed of SQSTM1/p62. We found that sodium tetrasulfide (Na₂S₄), a donor of RSS, strongly suppressed oxidative stress-dependent ALIS formation and subsequent parthanatos. On the other hand, the inhibitors of the RSS-producing enzymes, such as 3-mercaptopyruvate sulfurtransferase (3-MST) and cystathionine γ-lyase (CSE), clearly enhanced ALIS formation and parthanatos. Interestingly, we found that Na₂S₄ activated heat shock factor 1 (HSF1) by promoting its dissociation from heat shock protein 90 (HSP90), leading to accelerated transcription of HSP70. Considering that the genetic deletion of HSP70 allowed the enhanced ALIS formation, these findings suggest that RSS prevent parthanatos by specifically suppressing ALIS formation through induction of HSP70. Taken together, our results demonstrate a novel mechanism by which RSS prevent cell death, as well as a novel physiological role of RSS in contributing to protein quality control through HSP70 induction, which may lead to better understanding of the bioactivity of RSS.

70 kilodalton heat shock protein (Hsp70); Reactive sulfur species; aggresome; p62 (sequestosome 1(SQSTM1)); parthanatos.