The Dynamic Interface of Viruses with STATs

Abstract

Viruses commonly antagonize the antiviral type I interferon response by targeting signal transducer and activator of transcription 1 (STAT1) and STAT2, key mediators of interferon signaling. Other STAT family members mediate signaling by diverse cytokines important to infection, but their relationship with viruses is more complex. Importantly, virus-STAT interaction can be antagonistic or stimulatory depending on diverse viral and cellular factors. While STAT antagonism can suppress immune pathways, many viruses promote activation of specific STATs to support viral gene expression and/or produce cellular conditions conducive to infection. It is also becoming increasingly clear that viruses can hijack noncanonical STAT functions to benefit infection. For a number of viruses, STAT function is dynamically modulated through infection as requirements for replication change. Given the critical role of STATs in infection by diverse viruses, the virus-STAT interface is an attractive target for the development of antivirals and live-attenuated viral vaccines. Here, we review current understanding of the complex and dynamic virus-STAT interface and discuss how this relationship might be harnessed for medical applications.

Keywords: STAT signaling; STAT transcription factors; host-pathogen interactions; immune evasion; virus-host interactions.

FIG 1

Structure and signaling pathways of STATs. (A) Schematic representation of the conserved domain structure of STATs: N-terminal domain (ND), coiled-coil domain (CCD), DNA-binding domain (DBD), linker domain, Src homology 2 (SH2) domain, and C-terminal transactivation domain (TAD). The conserved C-terminal tyrosine phosphorylated by JAKs (pY) is indicated. (B) Diverse cytokines signal via a classical JAK-STAT paradigm. (1 and 2) Cytokine, growth factor, etc., bind to the cognate receptor (1), activating specific receptor-associated JAKs (2). (3) JAKs phosphorylate latent antiparallel STAT dimers (P in circles), inducing the formation of parallel dimers through reciprocal pY-SH2 interactions. (4) pY-STAT dimers translocate into the nucleus and bind specific DNA elements, activating gene expression. (5) pY-STATs are dephosphorylated by nuclear and cytoplasmic PTPs to turn off signaling. (6 and 7) STAT signaling is also negatively regulated (blunt arrows) by PIAS proteins (which bind STATs and prevent DNA binding, recruit corepressors, or mediate sumoylation) (6) and SOCS proteins (which are induced by pY-STATs and inhibit JAK kinase activity, bind competitively to STAT-binding sites on receptors, or target cytokine receptors and JAKs for proteasomal degradation; dotted line) (7). Red line, negative regulation; black line, positive regulation. (8) STATs are also positively or negatively regulated by PTMs.

FIG 2

Examples of viruses with genomic STAT-binding sites. (A) The EBV LMP1 promoter contains STAT3 and STAT6 sites. Cytokines activating STAT3 (IL-6, IL-21, and IL-10) or STAT6 (IL-13 and IL-4) induce LMP1, promoting cell transformation. LMP1 upregulates IL-6, resulting in a positive-feedback loop. EBV Zta protein induces IL-13, and IL-13 induces LMP1 via STAT6. (B) HBV enhancer 1 contains a STAT3 site. Cytokines activating STAT3 (IL-6 and epidermal growth factor [EGF]) induce viral gene expression. HBV (including HBV X protein) induces STAT3 activation. (C) The HIV-1 LTR contains a STAT5 site that is activated by STAT5-activating cytokines (e.g., IL-2, GM-CSF, IL-7, and IL-15) to induce gene expression and viral reactivation; this is inhibited in cells expressing C-terminally truncated STAT5, which binds to the LTR site. (D) The B19V replication origin in inverted terminal repeats (ITRs) contains a STAT5 site, where EPO/hypoxia-activated pY-STAT3 recruits the minichromosome maintenance (MCM) complex to initiate replication. (E) The KSHV RTA promoter contains a STAT6 site; LANA mediates cleavage of the STAT6 C terminus, and cleaved STAT6 binds to the RTA promoter, repressing RTA expression to promote latency. During lytic infection, expressed RTA induces STAT6 degradation.

FIG 3

Noncanonical STAT functions. (A) U-STAT1 to -3, -5a/b, and -6 are reported to have intranuclear gene-regulatory function. (B) STAT1, -3, -5, and -6 localize to mitochondria and regulate metabolism, cancer cell growth and proliferation, the mitochondrial permeability transition pore, mitochondrial gene expression, and autophagy. (C and D) Cytoplasmic STAT3 inhibits PKR to repress autophagy induction (C) and stathmin to stabilize microtubules (D). (E) pY-STAT3 accumulates at focal adhesions in ovarian cancer cells, potentially contributing to invasiveness. (F) U-STAT5a/b localize to the ER and Golgi apparatus and promote structural integrity. (G) STAT6 is recruited to the ER by STING following viral nucleic acid detection and is phosphorylated by non-JAK kinases before translocation to the nucleus to activate gene expression. (H) Cytoplasmic STAT4 promotes type I IFN induction in response to RNA viruses by binding the E3 ligase CHIP to protect RIG-I from proteasomal degradation.