An atypical E3 ligase zinc finger protein 91 stabilizes and activates NF-kappaB-inducing kinase via Lys63-linked ubiquitination.
The NF-κB transcription factors control many physiological processes, including inflammation, immunity, and apoptosis. Its activity contributes to the development of various cell malignancies. NF-κB-inducing kinase (NIK) plays a pivotal role in NF-κB activation. However, the molecular mechanism to stabilize and activate NIK remains elusive, although it is known that cIAP1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate NIK for degradation. Here, we report a novel NF-κB-related zinc finger protein 91 (ZFP91) that stabilizes and activates NIK in a ubiquitination-dependent manner. We show that ZFP91 interacts with and promotes the Lys(63)-linked ubiquitination of NIK and subsequent processing of p100 to p52. The results of in vitro biochemical assays indicate that ZFP91 functions as an E3 ligase directly to NIK. Remarkably, the ubiquitination of NIK coincides with its Thr(559) phosphorylation. Furthermore, knockdown of ZFP91 expression by RNA interference inhibits the CD40 ligation-induced activation of NIK and p100 processing as well as the expression of noncanonical NF-κB target genes. These data clearly indicate that ZFP91 is an important regulator of the noncanonical NF-κB pathway.
Jin
Xuejun
X
Center for Molecular Cancer Research, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungbuk 363-883, Republic of Korea.
Jin
Hong Ri
HR
Jung
Haeng Sun
HS
Lee
Se Jeong
SJ
Lee
Jeong-Hyung
JH
Lee
Jung Joon
JJ
D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C494832:BIRC3 protein, human; C553044:ZFP91 protein, human