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A novel nuclear zinc finger protein EZI enhances nuclear retention and transactivation of STAT3.

ABSTRACT: A novel cDNA EZI isolated as an oncostatin M- inducible gene encoded a protein containing 12 C2H2-type zinc fingers. EZI was found to transactivate the promoters that are also responsive to STAT3 and activated the acute phase response element (APRE) synergistically with STAT3. Co-immunoprecipitation demonstrated the association of EZI with STAT3, which was mediated by the N-terminal region (1-183) of EZI. The EZI mutant lacking this region showed reduced transcriptional activity, indicating that EZI and STAT3 function cooperatively through physical interaction. While EZI predominantly localized in the nucleus and enhanced the nuclear localization of STAT3, the EZI mutant lacking 11 zinc finger motifs failed to translocate into the nucleus and also inhibited nuclear localization of STAT3 as well as STAT3-mediated transactivation. These results indicate that EZI is a novel nuclear zinc finger protein that augments STAT3 activity by keeping it in the nucleus.

SUBMITTER: Nakayama K

PROVIDER: S-EPMC137188 | biostudies-literature | 2002 Nov

REPOSITORIES: biostudies-literature

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A novel nuclear zinc finger protein EZI enhances nuclear retention and transactivation of STAT3.

Nakayama Koh K Kim Kyung-Woon KW Miyajima Atsushi A

The EMBO journal 20021101 22

A novel cDNA EZI isolated as an oncostatin M- inducible gene encoded a protein containing 12 C2H2-type zinc fingers. EZI was found to transactivate the promoters that are also responsive to STAT3 and activated the acute phase response element (APRE) synergistically with STAT3. Co-immunoprecipitation demonstrated the association of EZI with STAT3, which was mediated by the N-terminal region (1-183) of EZI. The EZI mutant lacking this region showed reduced transcriptional activity, indicating that ...[more]

PMID: 12426389

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Project description:Given the unprecedented scale of the recent Ebola and Zika viral epidemics, it is crucial to understand the biology of host factors with broad antiviral action in order to develop novel therapeutic approaches. Here, we look into one such factor: zinc finger antiviral protein (ZAP) inhibits a variety of RNA and DNA viruses. Alternative splicing results in two isoforms that differ at their C termini: ZAPL (long) encodes a poly(ADP-ribose) polymerase (PARP)-like domain that is missing in ZAPS (short). Previously, it has been shown that ZAPL is more antiviral than ZAPS, while the latter is more induced by interferon (IFN). In this study, we discovered and confirmed the expression of two additional splice variants of human ZAP: ZAPXL (extralong) and ZAPM (medium). We also found two haplotypes of human ZAP. Since ZAPL and ZAPS have differential activities, we hypothesize that all four ZAP isoforms have evolved to mediate distinct antiviral and/or cellular functions. By taking a gene-knockout-and-reconstitution approach, we have characterized the antiviral, translational inhibition, and IFN activation activities of individual ZAP isoforms. Our work demonstrates that ZAPL and ZAPXL are more active against alphaviruses and hepatitis B virus (HBV) than ZAPS and ZAPM and elucidates the effects of splice variants on the action of a broad-spectrum antiviral factor.IMPORTANCE ZAP is an IFN-induced host factor that can inhibit a wide range of viruses, and there is great interest in fully characterizing its antiviral mechanism. This is the first study that defines the antiviral capacities of individual ZAP isoforms in the absence of endogenous ZAP expression and, hence, cross talk with other isoforms. Our data demonstrate that ZAP is expressed as four different forms: ZAPS, ZAPM, ZAPL, and ZAPXL. The longer ZAP isoforms better inhibit alphaviruses and HBV, while all isoforms equally inhibit Ebola virus transcription and replication. In addition, there is no difference in the abilities of ZAP isoforms to enhance the induction of type I IFN expression. Our results show that the full spectrum of ZAP activities can change depending on the virus target and the relative levels of basal expression and induction by IFN or infection.

Dataset Information

A novel nuclear zinc finger protein EZI enhances nuclear retention and transactivation of STAT3.

Publications

A novel nuclear zinc finger protein EZI enhances nuclear retention and transactivation of STAT3.

Similar Datasets

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