TRIM8 modulates STAT3 activity through negative regulation of PIAS3

Fumihiko Okumura,Yui Matsunaga,Yuta Katayama,Keiichi I Nakayama,Shigetsugu Hatakeyama

doi:10.1242/jcs.068981

Abstract

TRIM8 is a member of the protein family defined by the presence of a common domain structure composed of a tripartite motif: a RING-finger, one or two B-box domains and a coiled-coil motif. Here, we show that TRIM8 interacts with protein inhibitor of activated STAT3 (PIAS3), which inhibits IL-6-dependent activation of STAT3. Ectopic expression of TRIM8 cancels the negative effect of PIAS3 on STAT3, either by degradation of PIAS3 through the ubiquitin-proteasome pathway or exclusion of PIAS3 from the nucleus. Furthermore, expression of TRIM8 in NIH3T3 cells enhances Src-dependent tumorigenesis. These findings indicate that TRIM8 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3.

Highlights

The ubiquitin-mediated proteolytic pathway has an important role in the elimination of short-lived regulatory proteins (Peters, 1998), including those that contribute to the cell cycle, cellular signaling in response to environmental stress or extracellular ligands, morphogenesis, secretion, DNA repair and organelle biogenesis (Hershko and Ciechanover, 1998)
TRIM8 interacts with protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) Yeast two-hybrid screening was performed to identify proteins that interact with TRIM8
To determine whether TRIM8 interacts with PIAS3 in mammalian cells, FLAG-tagged full-length TRIM8 and HAtagged PIAS3 were expressed in HEK293T cells

Summary

Introduction

The ubiquitin-mediated proteolytic pathway has an important role in the elimination of short-lived regulatory proteins (Peters, 1998), including those that contribute to the cell cycle, cellular signaling in response to environmental stress or extracellular ligands, morphogenesis, secretion, DNA repair and organelle biogenesis (Hershko and Ciechanover, 1998). The system responsible for the attachment of ubiquitin to the target protein consists of several components that act in concert (Hershko and Ciechanover, 1992; Scheffner et al, 1995), including a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin-protein isopeptide ligase (E3). E3 is thought to be the component of the ubiquitin conjugation system that is most directly responsible for substrate recognition (Scheffner et al, 1995). On the basis of structural similarity, E3 enzymes have been classified into three families: the HECT (homologous to E6-AP COOH terminus) family (Hershko and Ciechanover, 1998; Huibregtse et al, 1995), the RING-finger-containing protein family (Freemont, 2000; Joazeiro and Weissman, 2000; Lorick et al, 1999) and the U-box family (Aravind and Koonin, 2000; Cyr et al, 2002; Hatakeyama et al, 2001). Many TRIM proteins are induced by type I and type II interferons (IFNs), suggesting that TRIM proteins have an important role in anti-viral and anti-microbial systems (Rajsbaum et al, 2008)

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Discussion

Conclusion