Poly-ubiquitination in TNFR1-mediated necroptosis

Abstract

Tumor necrosis factor (TNF) is a master pro-inflammatory cytokine, and inappropriate TNF signaling is implicated in the pathology of many inflammatory diseases. Ligation of TNF to its receptor TNFR1 induces the transient formation of a primary membrane-bound signaling complex, known as complex I, that drives expression of pro-survival genes. Defective complex I activation results in induction of cell death, in the form of apoptosis or necroptosis. This switch occurs via internalization of complex I components and assembly and activation of secondary cytoplasmic death complexes, respectively known as complex II and necrosome. In this review, we discuss the crucial regulatory functions of ubiquitination—a post-translational protein modification consisting of the covalent attachment of ubiquitin, and multiples thereof, to target proteins—to the various steps of TNFR1 signaling leading to necroptosis.

30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

“…The TNF receptor (TNFR) induces a well-understood IKK induction process. TNF stimulation of TNFR recruits the RIP-1, TRADD, TRAF2, cIAP, TAB, and TAK1 proteins into a megacomplex with the linear ubiquitin assembly complex (LUBAC) stabilized by linear and K63-linked polyubiquitin chains (Dondelinger et al, 2016). Then IKK is incorporated, causing ubiquitination of NEMO and phosphorylation of IKK that induce its kinase activity (Hayden and Ghosh, 2008).…”

“…The specific composition of the megacomplex depends on specific ubiquitin modifications. This, in turn, determines whether TNFR engagement causes NF-κB induction and survival or an alternative fate in which recruitment of RIP kinases 1 and 3 induce cell death instead of NF-κB (Dondelinger et al, 2016). The RIP protein family, RIPs 1–7, are adaptors and kinases that transmit signals from a wide variety of surface receptors and intracellular stress sensors to transcriptional mediators including Jnk, Erk, and p38 and NF-κB as well as mediators of necrotic death (Meylan and Tschopp, 2005).…”

Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis

“…In addition, contribution of RIPK1 to NFkB activation does not require its catalytic kinase activity [19, 20]. The subject of RIPK1 poly-ubiquitination is discussed comprehensively in multiple recent reviews [21-23]. …”

Programmed cell death as a defence against infection

“…For example, apoptosis 1,2 is a non-lytic and typically immunologically silent form of cell death. On the other hand, programmed lytic cell death is highly inflammatory, and includes necroptosis 3–5 , pyroptosis 6 , and the rapid release of so-called neutrophil extracellular traps (NETs) in a process known as NETosis 7 . The elimination of host immune cells by programmed cell death can be thought to benefit an infecting pathogen 8 .…”