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Updated: Jun 25, 2026

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
Published on: May 10, 2022
TRAF6 promotes ubiquitination and regulated intramembrane proteolysis of IL-1R1
Ciara Twomey1, Si Qian, Justin V McCarthy
1Signal Transduction Laboratory, Biochemistry Department, ABCRF, Cavanagh Pharmacy Building, University College Cork, Cork, Ireland.
Abstract:
It has recently been shown that Interleukin-1 receptor, type 1, an essential regulator of inflammation and inate immunity, undergoes regulated intramembrane proteolysis (RIP). Although IL-1R1-mediated intracellular signalling has been well studied, very little is known about how RIP of IL-1R1 is modulated. In this study, by using wild-type TRAF6 and TRAF6 mutants that are defective in its ubiquitin ligase activity, we show for the first time that TRAF6 induces ubiquitination of IL-1R1. We further demonstrate that of all TRAF family members examined, TRAF6 preferentially ubiquitinates IL-1R1. Moreover, we show that TRAF6 ubiquitin ligase activity and ubiquitination of IL-1R1 are positively correlated with IL-1R1 ectodomain shedding and subsequent gamma-secretase cleavage. Our results indicate that TRAF6-mediated ubiquitination of IL-1R1 has a decisive role in IL-1R1 signalling and propose a molecular mechanism whereby TRAF6 promotes ubiquitination and RIP of IL-1R1 through its ubiquitin ligase activity.
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