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Molecular and Cellular Biology, June 2005, p. 4716-4726, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4716-4726.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Ankyrin Repeat and SOCS Box 3 (ASB3) Mediates Ubiquitination and Degradation of Tumor Necrosis Factor Receptor II

Alicia S. Chung,1 Ying-jie Guan,2 Zheng-Long Yuan,2 Jorge E. Albina,2 and Y. Eugene Chin1,2*

Department of Molecular and Cell Biology and Biochemistry,1 Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, Rhode Island 029032

Received 15 December 2004/ Returned for modification 14 January 2005/ Accepted 14 February 2005

Ankyrin repeat and SOCS box (ASB) family members have a C-terminal SOCS box and an N-terminal ankyrin-related sequence of variable repeats belonging to the SOCS superfamily. While SH2-domain-bearing SOCS proteins are mainly involved in the negative feedback regulation of the protein tyrosine kinase-STAT pathway in response to a variety of cytokines, the roles of ASB family members remain largely unknown. To investigate ASB functions, we screened for ASB3-interacting factors by using antibody array technology and identified tumor necrosis factor receptor II (TNF-R2) as an ASB3 binding target. ASB3 expression and activities are required for (i) TNF-R2 ubiquitination both in vivo and in vitro, (ii) TNF-R2 proteolysis via the proteasome pathway, and (iii) the inhibition of TNF-R2-mediated Jun N-terminal protein kinase (JNK) activation. While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-{alpha} by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation.

* Corresponding author. Mailing address: Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903. Phone: (401) 444-0172. Fax: (401) 444-3278. E-mail: y_eugene_chin{at}brown.edu.

Molecular and Cellular Biology, June 2005, p. 4716-4726, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4716-4726.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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