ZNF216 Is an A20-like and I��B Kinase ��-Interacting Inhibitor of NF��B Activation

The transcription factor NF??B plays important roles in immune regulation, inflammatory responses, and anti-apoptosis. Activation of NF??B requires the activity of I??B kinase, a kinase complex that contains two catalytic subunits, IKK?? and IKK??, and a non-enzymatic regulatory subunit, IKK??. To understand how NF??B activation is regulated at the IKK?? level, we searched for IKK??-interacting proteins by the yeast two-hybrid system. This search identified ZNF216, a zinc finger protein with unknown biological functions. ZNF216 contains an A20-like zinc finger domain (ZnF-A20) at its N terminus and an AN1-like domain (ZnF-AN1) at its C terminus. Similar to A20, ZNF216 interacted with IKK??, RIP, and TRAF6 in co-immunoprecipitation experiments. Domain mapping experiments indicated that the ZnF-A20 domain was responsible for interacting with IKK?? and RIP, whereas the ZnF-AN1 domain interacted with TRAF6. ZNF216 inhibited NF??B activation triggered by overexpression of RIP and TRAF6 but not of p65. ZNF216 also inhibited tumor necrosis factor (TNF)-, interleukin-1-, and Toll-like receptor 4-induced NF??B activation in a dose-dependent manner. The ZnF-A20 domain was essential for ZNF216-mediated inhibition of NF??B activation. The ZnF-A20 and ZnF-AN1 domains of ZNF216 could interact with each other, whereas ZNF216 could form homo-oligomers or hetero-oligomers with A20. Unlike A20, which inhibits TNF-induced apoptosis, overexpression of ZNF216 sensitized cells to TNF-induced apoptosis. Our findings suggest that ZNF216 and A20 have redundant and distinct roles in regulating NF??B activation and apoptosis.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000220747900137&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701SCI(E)EIPubMed661616847-1685327