TRAF6 promotes ubiquitination and regulated intramembrane proteolysis of IL-1R1.
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.
Twomey
Ciara
C
Signal Transduction Laboratory, Biochemistry Department, ABCRF, Cavanagh Pharmacy Building, University College Cork, Cork, Ireland.
Qian
Si
S
McCarthy
Justin V
JV
D000595:Amino Acid Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D008239:Lysine; D008969:Molecular Sequence Data; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
C508590:IL1R1 protein, human; D053573:Receptors, Interleukin-1 Type I; D048029:TNF Receptor-Associated Factor 6; D008239:Lysine