No abstract

Members of the suppressor of cytokine signaling (SOCS) family of signaling molecules regulate the activation of cytokine signaling. Experimental evidence indicates that SOCS expression is induced by cytokines and pro-inflammatory stimuli and is controlled at both the transcriptional and post-transcriptional levels. SOCS proteins are unstable and seem to be rapidly degraded by proteasomal pathways. However, the mechanisms by which SOCS protein levels are regulated remain unclear. Here, we show that TRIM8/GERP, a RING finger protein, interacts with SOCS-1 in vitro and in vivo. TRIM8/GERP, previously identified as a new member of the family of proteins containing a tripartite motif (TRIM), is a 551-amino acid RING finger protein conserved across species. TRIM8/GERP expression can be induced by interferon-␥ in epithelial and lymphoid cells. Coexpression of TRIM8/GERP with SOCS-1 decreases SOCS-1 protein stability and levels. Functionally, expression of TRIM8/GERP decreases the repression of interferon-␥ signaling mediated by SOCS-1. These data suggest that TRIM8/GERP may be a regulator of SOCS-1 function.Cytokines control many different cellular functions, including proliferation, differentiation, and gene expression (1, 2). Moreover, they participate in the pathophysiology of viral infections, play a central role in the development of the hematopoietic system, and have been implicated in the pathogenesis of autoimmune diseases (3, 4). The biological response of a cell to cytokines involves a complex network of signal transduction machinery. Signaling is initiated by the oligomerization of cognate cytokine receptors expressed on the surface of target cells (5), which triggers the activation of members of the JAK 1 family of protein-tyrosine kinases that constitutively associate with the cytokine receptor. Subsequently, JAKs can phosphorylate tyrosine residues present in the cytoplasmic regions of the receptors. These phosphorylated tyrosines then act as docking sites for signaling molecules, such as members of the STAT family of transcription factors (6).The intensity and duration of cytokine signaling seems to be regulated by several mechanisms. It is now known that at least three different classes of negative regulators contribute to cytokine inhibition: (i) the SH2-containing protein-tyrosine phosphatases 1 and 2 (7, 8), (ii) the protein inhibitors of activated STATs, and (iii) the suppressor of cytokine signaling (SOCS protein) (9 -13). Experimental data suggest that (i) SOCS genes are induced by cytokines; (ii) SOCS molecules can inhibit cytokine signaling by binding to downstream signaling molecules such as JAK kinases (14 -16); (iii) deregulated expression of SOCS proteins perturbs cytokine-related cellular proliferation and hematopoietic differentiation in murine tissues (17). Mice lacking SOCS-1 die shortly after birth from hepatic necrosis (18 -20). Data suggest that this lethality is due, at least in part, to hypersensitivity to IFN-␥ signaling. SOCS-2-deficient mice seem healthy after birth but develop a...

Recent studies have suggested that signaling initiated by the activation of Ag receptors and signaling activated through cytokine receptors may be regulated by a common set of inhibitory proteins. Suppressor of cytokine signaling 3 (SOCS-3), which has previously been demonstrated to inhibit cytokine signaling, is induced on TCR ligation. Overexpression of SOCS-3 can inhibit transcription driven by the IL-2 promoter in response to T cell activation. This inhibitory activity correlates with the suppression of calcineurin-dependent dephosphorylation and activation of the IL-2 promoter binding transcription factor, NFATp. Infection of primary murine T cells with a retrovirus encoding SOCS-3 blocks their IL-2 production in response to activation. Interestingly, SOCS-3 was found to coimmunoprecipitate with the catalytic subunit of calcineurin. These studies suggest that SOCS-3 may regulate T cell function as part of a negative feedback loop.