Two programmed cell destruction pathways: osmotic stresses-induced necroptosis and SARM1-mediated axonal degeneration

Datum

12.12.2023

Zeit

13:00 - 14:00

Sprecher

Wenbin Zhang

Zugehörigkeit

NIBS & Peking University

Sprache

en

Hauptthema

Biologie

Host

Tony Hyman

Beschreibung

Necroptosis is a tightly regulated form of cell death that plays a critical role in the pathogenesis of various diseases, including neurologic, cardiovascular, as well as numerous inflammatory diseases. During necroptosis, affected cells exhibit membrane rupture, resulting in the release of intracellular components. The activation and execution of necroptosis involve a complex series of biochemical reactions within the cell. The classical necroptosis signaling pathway is primarily initiated by stimuli from the tumor necrosis factor family, such as TNF-α, which induce necrotic cell death through the RIPK1-RIPK3-MLKL pathway. Recently, our study has uncovered an additional mechanism of necroptosis activation in response to extracellular osmotic stresses. Notably, unlike previously identified necroptosis inducers, osmotic stress triggers necroptosis by directly activating RIPK3 kinase activity, which is facilitated by an increase in cytosolic pH mediated by the Na+/H+ exchanger SLC9A1. SARM1 is a well-known mediator of axonal degeneration and has been reported to deplete NAD+ levels following nerve injury through its NADase activity. Studies have shown that deficiency of SARM1 can attenuate axon degeneration in various experimental models. Here, we have identified a class of potent SARM1 activators. These activators have been observed to induce SARM1-dependent cell death and axon degeneration in 293T cells and dorsal root ganglia (DRG), respectively, at specific concentrations. Interestingly, unlike previously reported SARM1 activators that interact directly with the ARM domain, we found that disruption of the NMN/NAD+ binding site within the ARM domain does not hinder the ability of this activator to induce SARM1 activation. Instead, this activator activities SARM1 NADase through a liquid-to-solid phase transition. This finding suggests a model in which SARM1 condensation leads to NADase activation and subsequent axon degeneration. Notably, this mechanism shares similarities with the activation behavior observed in Bacterial TIR enzymes during their antiphage responses.

Letztmalig verändert: 13.12.2023, 07:37:38