NF-?B essential modulator (NEMO) interaction with linear and lys-63 ubiquitin chains contributes to NF-?B activation.

ABSTRACT: The I?B kinase (IKK) complex acts as a gatekeeper of canonical NF-?B signaling in response to upstream stimulation. IKK activation requires sensing of ubiquitin chains by the essential IKK regulatory subunit IKK?/NEMO. However, it has remained enigmatic whether NEMO binding to Lys-63-linked or linear ubiquitin chains is critical for triggering IKK activation. We show here that the NEMO C terminus, comprising the ubiquitin binding region and a zinc finger, has a high preference for binding to linear ubiquitin chains. However, immobilization of NEMO, which may be reminiscent of cellular oligomerization, facilitates the interaction with Lys-63 ubiquitin chains. Moreover, selective mutations in NEMO that abolish association with linear ubiquitin but do not affect binding to Lys-63 ubiquitin are only partially compromising NF-?B signaling in response to TNF? stimulation in fibroblasts and T cells. In line with this, TNF?-triggered expression of NF-?B target genes and induction of apoptosis was partially compromised by NEMO mutations that selectively impair the binding to linear ubiquitin chains. Thus, in vivo NEMO interaction with linear and Lys-63 ubiquitin chains is required for optimal IKK activation, suggesting that both type of chains are cooperating in triggering canonical NF-?B signaling.

SUBMITTER: Hadian K 

PROVIDER: S-EPMC3138271 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature