SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome

Abstract

The regulation of cytokine signaling is critical for controlling cellular proliferation and activation during an immune response. SOCS-1 is a potent inhibitor of Jak kinase activity and of signaling initiated by several cytokines. SOCS-1 protein levels are tightly regulated, and recent data suggest that SOCS-1 may regulate the protein levels of some signaling proteins by the ubiquitin proteasome pathway; however, the cellular mechanism by which SOCS-1 directs proteins for degradation is unknown. In this report, SOCS-1 is found to colocalize and biochemically copurify with the microtubule organizing complex (MTOC) and its associated 20S proteasome. The SOCS-1 SH2 domain is required for the localization of SOCS-1 to the MTOC. Overexpression of SOCS-1 targets Jak1 in an SH2-dependent manner to a perinuclear distribution resembling the MTOC-associated 20S proteasome. Analysis of MTOCs fractionated from SOCS-1-deficient cells demonstrates that SOCS-1 may function redundantly to regulate the localization of Jak1 to the MTOC. Nocodazole inhibits the protein turnover of SOCS-1, demonstrating that the minus-end transport of SOCS-1 to the MTOC-associated 20S proteasome is required to regulate SOCS-1 protein levels. These data link SOCS-1 directly with the proteasome pathway and suggest another function for the SH2 domain of SOCS-1 in the regulation of Jak/STAT signaling.

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SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome

We thank Jonathan Barasch, Steve Greenberg, Gregg Gundersen, and Fred Chang for their technical discussions in cell biology; Raphael Clynes for the use of his fluorescence microscope; Theresa Swayne and Sudhindra Swamy of the Columbia University Optical Microscope Facility for their assistance in confocal imaging; and Jean Gautier and Chris Schindler for the use of their analytical ultracentrifuges.

B. Vuong and A. Banks were supported by grants (5T32 AI07161-20 and 5T32 AI07525-04) provided by the National Institutes of Health. P. Rothman was supported by NIH grant P01 AI50514 and the Arthritis Foundation.