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J. Biol. Chem., Vol. 281, Issue 35, 25850-25866, September 1, 2006

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The Interaction of Piasy with Trim32, an E3-Ubiquitin Ligase Mutated in Limb-girdle Muscular Dystrophy Type 2H, Promotes Piasy Degradation and Regulates UVB-induced Keratinocyte Apoptosis through NFB^*

Amador Albor¹, Sally El-Hizawi, Elizabeth J. Horn², Melanie Laederich, Patrick Frosk^¶, Klaus Wrogemann^¶, and Molly Kulesz-Martin³

From the Department of Dermatology and Program in Cell and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 and the ^¶Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada

Protein inhibitors of activated STATs (PIAS) family members are ubiquitin-protein isopeptide ligase-small ubiquitin-like modifier ligases for diverse transcription factors. However, the regulation of PIAS protein activity in cells is poorly understood. Previously, we reported that expression of Trim32, a RING domain ubiquitin-protein isopeptide ligase-ubiquitin ligase mutated in human limb-girdle muscular dystrophy type 2H (LGMD2H) and Bardet-Biedl syndrome, is elevated during mouse skin carcinogenesis, protecting keratinocytes from apoptosis induced by UVB and tumor necrosis factor- (TNF). Here we report that Trim32 interacts with Piasy and promotes Piasy ubiquitination and degradation. Ubiquitination of Piasy by Trim32 could be reproduced in vitro using purified components. Their interaction was induced by treatment with UVB/TNF and involved redistribution of Piasy from the nucleus to the cytoplasm, where it accumulated in cytoplasmic granules that colocalized with Trim32. Piasy destabilization and ubiquitination required an intact RING domain in Trim32. The LGMD2H-associated missense point mutation prevented Trim32 binding to Piasy, and human Piasy failed to colocalize with human Trim32 in fibroblasts isolated from an LGMD2H patient. Trim32 expression increased the transcriptional activity of NFB in epidermal keratinocytes, both under basal treatment and after UVB/TNF treatment. Conversely, Piasy inhibited NFB activity under the same conditions and sensitized keratinocytes to apoptosis induced by TNF and UVB. Our results indicate that, by controlling Piasy stability, Trim32 regulates UVB-induced keratinocyte apoptosis through induction of NFB and suggests loss of function of Trim32 in LGMD2H.

Received for publication, February 22, 2006 , and in revised form, June 19, 2006.

^* This work was supported by National Institutes of Health Grant CA098577 and Oregon Health and Science University Cancer Institute Core Grant CA69533. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

² Present address: National Psoriasis Foundation, Portland, OR.

¹ To whom correspondence may be addressed: Dept. of Dermatology, Mail Code OP06, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-418-4271; Fax: 503-418-4266; E-mail: albora{at}ohsu.edu. ³ To whom correspondence may be addressed. Tel.: 503-494-9933; Fax: 503-418-4266; E-mail: kuleszma{at}ohsu.edu.

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