Viral exploitation of host SOCS protein functions

Abstract

Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

FIG. 1.

SOCS protein structure. All SOCS proteins contain a central SH2 domain and a C-terminal SOCS box. The SH2 domain determines the target of each SOCS protein by binding specific phosphorylated (P) tyrosine residues on its preferred substrate (commonly JAK proteins). The SOCS box interacts with ubiquitinating machinery, including Elongin B (EB), Elongin C (EC), Cullin5, RING-box-2 (Rbx2), and an E2 ubiquitin-conjugating enzyme. By bringing the bound substrate into proximity with ubiquitinating machinery, the SOCS protein facilitates ubiquitination (U) of target proteins, thereby marking them for degradation by the proteosome. Certain SOCS proteins also contain an N-terminal kinase inhibitory region (KIR). The KIR is thought to function as a pseudosubstrate to inhibit the kinase activity of proteins that are bound by, or in close proximity to, the SOCS protein.

FIG. 2.

SOCS proteins negatively regulate the JAK/STAT pathway. (A) Composition of selected JAK/STAT pathways. (B) Function of JAK/STAT pathway. Cytokine stimulation of cell surface receptors activates receptor-associated JAK proteins by phosphorylation (P). Activated JAKs phosphorylate receptor cytoplasmic domains (1), which leads to the recruitment of cytoplasmic STAT proteins (2). Recruited STATs are activated by JAK phosphorylation (3), allowing them to dimerize (4) and enter the nucleus as a transcription factor complex to induce the expression of target genes. Gene targets often include both immune effectors and SOCS proteins. (C) SOCS proteins. SOCS proteins negatively regulate this pathway by binding specific substrates within the JAK/STAT receptor complex and terminating pathway activation in one of the following ways: competition with recruited STAT proteins for shared phosphotyrosine residues (1), kinase inhibitory region (KIR)-mediated inhibition of JAK activity (2), or SOCS box-mediated ubiquitination and degradation of bound receptor components (3).