Ubiquitination in TNF signaling

The role of ubiquitination in TNF signaling. TNF binding to TNFR1 triggers the formation of the TNFR complex I, which comprises TRAF2, TRADD, UBE2D, cIAP1/2, and RIPK1. Within TNFR complex I, RIPK1 undergoes ubiquitination with M1-, K11-, K48-, and K63-linked ubiquitin chains, including mixed and branched chains. This ubiquitination of RIPK1 serves to stabilize TNFR complex I and enables the transmission of downstream signaling through LUBAC-induced M1-linked ubiquitination of its constituents (HOIP, HOIL-1, and SHARPIN) and NEMO, resulting in the activation of the NF-κB (p65-p50) or MAPK signaling pathway to promote cell survival and proinflammatory gene expression. Extended TNF signaling triggers additional cytotoxic pathways: the apoptosis pathway mediated by the TNFR1 complex II, which includes RIPK1-FADD-Caspase8 and the necrosome-mediated pathway via the formation of the RIPK1–RIPK3–MLKL complex. Ubiquitinated substrates and free ester-linked branched chains catalyzed by LUBAC may play a central role in mediating inflammation and cell death signaling pathways

Publication

The emerging roles of non-canonical ubiquitination in proteostasis and beyond (2024) Yoshino Akizuki, et al. J Cell Biol. 2024 May 06;223(5). Figure: F4. Homo sapiens

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