Roles of p97/VCP in linear ubiquitin mediated NF-kappaB activation

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The LUBAC ubiquiin ligase is composed of three subunits, HOIP, HOIL-1L and SHARPIN. LUBAC possesses multiple domains, but the role of the PUB domain that exists in the N-terminal region of HOIP had not been addressed. The PUB domain has been identified as a binding domain of p97/VCP. Since p97/VCP has shown to regulate NF-kappaB activation negatively, we examined the role of the PUB domain in LUBAC mediated NF-kappaB activation. To our surprise, in cells expressing a HOIP mutant, which cannot bind p97/VCP, both NF-kappaB activation and linear polyubiquitination of NEMO mediated by TNF-alpha were augmented. We then sought proteins bound to the PUB domain of HOIP and found that two deubiquitinases, OTULIN and CYLD, that specifically cleaved linear chains as interacting proteins of HOIP PUB. Both OTULIN and CYLD bind to the PUB domain of HOIP directly and down-regulated LUBAC-mediated NF-kappaB activation.