TRIM32 Protein Sensitizes Cells to Tumor Necrosis Factor (TNF alpha)-induced Apoptosis via Its RING Domain-dependent E3 Ligase Activity against X-linked Inhibitor of Apoptosis (XIAP)

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TRIM32, which belongs to the tripartite motif (TRIM) protein family, has the RING finger, B-box, and coiled-coil domain structures common to this protein family, along with an additional NHL domain at the C terminus. TRIM32 reportedly functions as an E3 ligase for actin, a protein inhibitor of activated STAT y (PIASy), dysbindin, and c-Myc, and it has been associated with diseases such as muscular dystrophy and epithelial carcinogenesis. Here, we identify a new substrate of TRIM32 and propose a mechanism through which TRIM32 might regulate apoptosis. Our overexpression and knockdown experiments demonstrate that TRIM32 sensitizes cells to TNF alpha-induced apoptosis. The RING domain is necessary for this pro-apoptotic function of TRM32 as well as being responsible for its E3 ligase activity. TRIM32 colocalizes and directly interacts with X-linked inhibitor of apoptosis (XIAP), a well known cancer therapeutic target, through its coiled-coil and NHL domains. TRIM32 overexpression enhances XIAP ubiquitination and subsequent proteasome-mediated degradation, whereas TRIM32 knockdown has the opposite effect, indicating that XIAP is a substrate of TRIM32. In vitro reconstitution assay reveals that XIAP is directly ubiquitinated by TRIM32. Our novel results collectively suggest that TRIM32 sensitizes TNF alpha-induced apoptosis by antagonizing XIAP, an anti-apoptotic downstream effector of TNF alpha signaling. This function may be associated with TRIM32-mediated tumor suppressive mechanism.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2011-07
Language
English
Article Type
Article
Keywords

NF-KAPPA-B; DYSTROPHY TYPE 2H; COILED-COIL PROTEIN; UBIQUITIN LIGASE; ANTIVIRAL ACTIVITY; CASPASE ACTIVITY; OPITZ-SYNDROME; GENE; FINGER; IAP

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.286, no.29, pp.25729 - 25738

ISSN
0021-9258
URI
http://hdl.handle.net/10203/97354
Appears in Collection
BS-Journal Papers(저널논문)
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