Abstract
RIPK1, RIPK3, ZBP1 and TRIF, the four mammalian proteins harboring RIP homotypic interaction motif (RHIM) domains, are key components of inflammatory signaling and programmed cell death. RHIM-domain protein activation is mediated by their oligomerization; however, mechanisms that promote a return to homeostasis remain unknown. Here we show that autophagy is critical for the turnover of all RHIM-domain proteins. Macrophages lacking the autophagy gene Atg16l1accumulated highly insoluble forms of RIPK1, RIPK3, TRIF and ZBP1. Defective autophagy enhanced necroptosis by Tumor necrosis factor (TNF) and Toll-like receptor (TLR) ligands. TNF-mediated necroptosis was mediated by RIPK1 kinase activity, whereas TLR3- or TLR4-mediated death was dependent on TRIF and RIPK3. Unexpectedly, combined deletion of Atg16l1 and Zbp1 accelerated LPS-mediated necroptosis and sepsis in mice. Thus, ZBP1 drives necroptosis in the absence of the RIPK1-RHIM, but suppresses this process when multiple RHIM-domain containing proteins accumulate. These findings identify autophagy as a central regulator of innate inflammation governed by RHIM-domain proteins.
Highlights
Programmed cell death plays a central role in dictating tolerogenic or immuno-stimulatory responses
We show that defective autophagy in macrophages leads to an accumulation of modified Receptor interacting protein kinase 1 (RIPK1), RIPK3, and TRIF in response to pro-inflammatory signals, precipitating inflammation and necroptosis in a stimulus-dependent manner (Figure 7—figure supplement 1B,C)
While RIPK1, RIPK3 and TRIF are well-established signaling factors required for necroptosis, our understanding of Z-DNA binding protein 1 (ZBP1) in this context is less developed
Summary
Programmed cell death plays a central role in dictating tolerogenic or immuno-stimulatory responses. To leverage these pathways therapeutically, it is critical to understand how immune-suppressive versus inflammatory modes of cell death (e.g. necroptosis and pyroptosis) are regulated. Receptor interacting protein kinase 1 (RIPK1) kinase activity drives caspase 8-dependent apoptosis as well as pro-inflammatory necroptosis dependent on RIPK3 and its substrate mixed lineage kinase domain like (MLKL) (Cho et al, 2009; He et al, 2009; Sun et al, 2012; Zhang et al, 2009; Zhao et al, 2012). Defective autophagy enhanced cytokine production and necroptosis driven by activators of RHIM-domain proteins. We identify autophagy as an upstream regulator of RHIM-domain proteins and reveal a non-canonical, immunosuppressive function of ZBP1 upon defective autophagy
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