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2018 ; 9
(6
): 592
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Triad3a induces the degradation of early necrosome to limit RipK1-dependent
cytokine production and necroptosis
#MMPMID29789521
Alturki NA
; McComb S
; Ariana A
; Rijal D
; Korneluk RG
; Sun SC
; Alnemri E
; Sad S
Cell Death Dis
2018[May]; 9
(6
): 592
PMID29789521
show ga
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.
|*Apoptosis
[MESH]
|*Proteolysis
[MESH]
|Animals
[MESH]
|Cytokines/*biosynthesis
[MESH]
|Inhibitor of Apoptosis Proteins/metabolism
[MESH]