Receptor interacting protein kinase 2–mediated mitophagy regulates inflammasome activation during virus infection

Abstract

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2−/− and Ripk2−/− mice are hypersusceptible to influenza A virus infection. Ripk2−/− cells displayed defective mitophagy leading to enhanced mitochondrial superoxide production and accumulation of damaged mitochondria resulting in increased NLRP3 inflammasome activation and IL-18 production. RIPK2 regulated mitophagy in a kinase-dependent manner by phosphorylating the mitophagy inducer ULK1. Accordingly, Ulk1−/− cells displayed enhanced mitochondrial superoxide production and caspase-1 activation. These results demonstrate a role for NOD2-RIPK2 signaling in protection against virally triggered immunopathology by negatively regulating NLRP3 inflammasome activation and IL-18 production via ULK1-dependent mitophagy.

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

“…10,48 In this study, SESN2 induced autophagosome formation and mitophagy activation through the conservation of ULK1 protein levels, rather than ULK1 phosphorylation upon stimulation, supporting a novel mechanism whereby ULK1-dependent mitophagy activation can be regulated by ULK1 protein stability. Upon stimulation, endogenous interaction with SESN2 and ULK1 was not observed when evaluated by co-IP with SESN2 antibody and western blot analysis (data not shown), suggesting that stimulation-dependent ULK1 translocation to mitochondria and maintenance of its protein levels may not be attributable to its association with SESN2.…”

“…[5][6][7][8] Accumulating data suggests that mitophagy has an essential role in the regulation of the innate immune response. [9][10][11][12] When mitophagy is impaired, the increase of damaged mitochondria caused by immune stimulators results in the generation of mitochondrial ROS (reactive oxygen species) and release of mitochondrial DNA, which induces hyperactivation of the NLRP3 inflammasome, and in turn leads to over-inflammation, tissue injury and increased mortality in the host. 9,10,12,13 Although a number of mitophagy-related factors have been identified, detailed mechanisms by which they take action are still largely unknown.…”

“…[9][10][11][12] When mitophagy is impaired, the increase of damaged mitochondria caused by immune stimulators results in the generation of mitochondrial ROS (reactive oxygen species) and release of mitochondrial DNA, which induces hyperactivation of the NLRP3 inflammasome, and in turn leads to over-inflammation, tissue injury and increased mortality in the host. 9,10,12,13 Although a number of mitophagy-related factors have been identified, detailed mechanisms by which they take action are still largely unknown. Recent studies on mitophagy in mammalian cell studies reveal that signal-dependent removal of damaged mitochondria by mitophagy requires 2 steps.…”

Human ULK1 Variation and Susceptibility toMycobacterium tuberculosisInfection

“…Autophagy has been shown to limit inflammasome activity, and inhibition of autophagy led to increased IL-1β secretion after infection with M. tuberculosis [44,47]. In addition, ULK1 has been demonstrated to negatively regulate NLRP3 and caspase-1 activity with decreases in interleukin 18 expression [48]. Our data suggest that ULK1 mediates TLR and M. tuberculosis-induced TNF secretion, but not NLRC4-mediated IL-1β production.…”

Immunologic manifestations of autophagy

“…Autophagy suppresses inflammasome activation ( Figure 1C and refs. [21][22][23][24][25]. Loss of autophagy (ATG16L1 deficiency) increases IL-1β levels in a mouse model of gut inflammation (21).…”