Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Apr 11:10:732.
doi: 10.3389/fimmu.2019.00732. eCollection 2019.

SOCS and Herpesviruses, With Emphasis on Cytomegalovirus Retinitis

Christine I Alston  1   2 , Richard D Dix  1   2
Affiliations
Review

SOCS and Herpesviruses, With Emphasis on Cytomegalovirus Retinitis

Christine I Alston et al. Front Immunol. .

Abstract

Suppressor of cytokine signaling (SOCS) proteins provide selective negative feedback to prevent pathogeneses caused by overstimulation of the immune system. Of the eight known SOCS proteins, SOCS1 and SOCS3 are the best studied, and systemic deletion of either gene causes early lethality in mice. Many viruses, including herpesviruses such as herpes simplex virus and cytomegalovirus, can manipulate expression of these host proteins, with overstimulation of SOCS1 and/or SOCS3 putatively facilitating viral evasion of immune surveillance, and SOCS suppression generally exacerbating immunopathogenesis. This is particularly poignant within the eye, which contains a diverse assortment of specialized cell types working together in a tightly controlled microenvironment of immune privilege. When the immune privilege of the ocular compartment fails, inflammation causing severe immunopathogenesis and permanent, sight-threatening damage may occur, as in the case of AIDS-related human cytomegalovirus (HCMV) retinitis. Herein we review how SOCS1 and SOCS3 impact the virologic, immunologic, and/or pathologic outcomes of herpesvirus infection with particular emphasis on retinitis caused by HCMV or its mouse model experimental counterpart, murine cytomegalovirus (MCMV). The accumulated data suggests that SOCS1 and/or SOCS3 can differentially affect the severity of viral diseases in a highly cell-type-specific manner, reflecting the diversity and complexity of herpesvirus infection and the ocular compartment.

Keywords: SOCS1; SOCS3; cytomegalovirus; herpesvirus; retinitis; suppressor of cytokine signaling.

PubMed Disclaimer

Figures

Figure 1
Figure 1
SOCS family proteins and their domains. Src homology 2 (SH2) domains (blue) govern target protein specificity by recognizing phosphorylated tyrosine residues flanked by specific sequences such as those on cytoplasmic residues of cytokine receptors. SOCS1 and SOCS3 exclusively contain kinase inhibitory regions (KIR, red), which bind and inhibit JAK proteins. Extended SH2 sequences (ESS, green) enhance binding specificity and affinities to phosphotyrosine residues. SOCS box domains (pink) recruit cellular Elongin BC, Cullin5, and RING-box-2 to form an E3 ubiquitin ligase complex, ubiquitinating target proteins for proteasomal degradation. PEST motifs (yellow) greatly decrease the half-lives of the proteins; see (35, 36) for predicted PEST domain locations. Amino acid (aa) lengths for Homo sapiens SOCS proteins are from the National Center for Biotechnology Information (NCBI) database (February 2019).
Figure 2
Figure 2
SOCS induction by and inhibition of the JAK/STAT pathway. (1) Extracellular cytokines cause dimerization of their cognate transmembrane receptors. This brings intracellular receptor-associated JAK proteins into proximity to cross-phosphorylate each other and tyrosine residues on the receptors. (2) STAT proteins dock at phosphotyrosines on intracellular receptor subunits. (3) JAK proteins phosphorylate STAT proteins, activating them. (4) Activated STAT proteins undock from their receptors, dimerize, and translocate to the nucleus. (5) STAT proteins act as transcription factors for dozens of immune targets, including SOCS. (6) Functioning in the cytoplasm, SOCS proteins can bind various phosphotyrosines on intracellular receptors, blocking STATs from their native docking sites. (7) With their KIR domains, SOCS1 and SOCS3 can inhibit the kinase activity of JAK proteins, preventing tyrosine phosphorylation of STAT proteins. (8) SOCS boxes facilitate ubiquitination of SOCS-bound protein targets for proteasomal degradation. Abbreviations: suppressor of cytokine signaling (SOCS), Janus kinase (JAK), signal transducers and activators of transcription (STAT), kinase inhibitory region (KIR). See Akhtar and Benveniste (5).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Pellett PE, Roizman B. Herpesviridae. In: Knipe DM, Howley PM, editors. Fields Virology. 6th ed. Philadelphia, PA: Lippencott Williams and Wilkins; (2013). p. 1802–22.
    1. Matsubara T, Pararajasegaram G, Wu G-S, Rao NA. Retinal microglia differentially express phenotypic markers of antigen-presenting cells in vitro. Invest Ophthalmol Vis Sci. (1999) 40:3186–93. - PubMed
    1. Alexander WS, Starr R, Metcalf D, Nicholson SE, Farley A, Elefanty AG, et al. . Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction. J Leukoc Biol. (1999) 66:588–92. 10.1002/jlb.66.4.588 - DOI - PubMed
    1. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. (2007) 7:454–65. 10.1038/nri2093 - DOI - PubMed
    1. Akhtar LN, Benveniste EN. Viral exploitation of host SOCS protein functions. J Virol. (2011) 85:1912–21. 10.1128/JVI.01857-10 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources