The E3 ubiquitin ligase MARCH8 negatively regulates IL-1β-induced NF-κB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation.
The proinflammatory cytokine interleukin-1 (IL-1) signals via type I IL-1 receptor (IL-1RI) and IL-1 receptor accessory protein (IL1RAP), which leads to activation of the transcription factor NF-κB and induction of a range of downstream proteins involved in inflammatory and immune responses. Here, we identified the E3 ubiquitin ligase membrane-associated RING-CH (MARCH8) as a suppressor of IL-1β-induced NF-κB- and MAPK-activation pathways. Overexpression of MARCH8 inhibits IL-1β-induced NF-κB and MAPK activation, whereas knockdown of MARCH8 has the opposite effect. Mechanistically, MARCH8 interacts with IL1RAP and targets its Lys512 for K48-linked polyubiquitination and degradation. Our findings suggest that MARCH8-mediated polyubiquitination and degradation of IL1RAP is an important mechanism for negative regulation of IL-1β-induced signaling pathways.
State Key Laboratory of Virology, College of Life Sciences,  Wuhan University, Wuhan 430072,  China.
Rui
R
Chen
Mi
M
Li
Yu
Y
Zhang
Qian
Q
Zhou
Hong-Bing
HB
Shu
D015870:Gene Expression / Q000276:immunology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D025821:Polyubiquitin / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology
C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D053583:Interleukin-1beta; D008565:Membrane Proteins; D016328:NF-kappa B; D025821:Polyubiquitin; C568898:MARCHF8 protein, human; D044767:Ubiquitin-Protein Ligases