TY - JOUR
T1 - Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis article
AU - Alturki, Norah A.
AU - McComb, Scott
AU - Ariana, Ardeshir
AU - Rijal, Dikchha
AU - Korneluk, Robert G.
AU - Sun, Shao Cong
AU - Alnemri, Emad
AU - Sad, Subash
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses.
AB - Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses.
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U2 - 10.1038/s41419-018-0672-0
DO - 10.1038/s41419-018-0672-0
M3 - Article
C2 - 29789521
AN - SCOPUS:85047600134
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 6
M1 - 592
ER -