title: Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1.
abstract: Previously, we found that two isoforms of the ZNF268 gene (ZNF268a and ZNF268b2, with and without the KRAB domain, respectively) might play distinct roles in normal epithelia and in cervical cancer. Here we further investigated that KRAB domain defined the function disparity in part by reinforcing nuclear localization of ZNF268a. We found that the A-box of KRAB alone retained major specific nuclear localization activity. In contrast, the B-box alone did not have nuclear localization activity but enhanced it significantly. Consistent with the critical function of the A-box, each mutation of six conserved residues (V9, V11, F13, E16, E17 and W18) in the A-box dramatically impaired nuclear localization activity. Furthermore, the unique nuclear localization activity of KRAB was verified in seven additional KRAB-containing zinc finger proteins (KRAB-ZFPs), suggesting that it is a universal feature of KRAB-ZFPs. Finally, KRAB exerted its unique nuclear localization activity by interacting with the RBCC domain of its corepressor KAP1. Our results have revealed a novel mechanism by which the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. Our study also suggests that loss of the KRAB domain in KRAB-ZFPs due to aberrant alternative splicing might contribute to carcinogenesis.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jinyang
authors.initials: J
authors.lastname: Cai
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Hu
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Ze
authors.initials: Z
authors.lastname: Chen
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.forename: Mingxiong
authors.initials: M
authors.lastname: Guo
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D012097:Repressor Proteins; C482295:ZNF268 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28