Beyond Tethering the Viral Particles: Immunomodulatory Functions of Tetherin (BST-2)

Abstract

Host response to viral infection is a highly regulated process involving engagement of various host factors, cytokines, chemokines, and stimulatory signals that pave the way for an antiviral immune response. The response is manifested in terms of viral sequestration, phagocytosis, and inhibition of genome replication, and, finally, if required, lymphocyte-mediated clearance of virally infected cells. During this process, cross-talk between viral and host factors can shape disease outcomes and immunopathology. Bone marrow stromal antigen 2 (BST-2), also know as tetherin, is induced by type I interferon produced in response to viral infections, as well as in certain cancers. BST-2 has been shown to be a host restriction factor of virus multiplication through its ability to physically tether budding virions and restrict viral spread. However, BST-2 has other roles in the host antiviral response. This review focuses on the diverse functions of BST-2 and its downstream signaling pathways in regulating host immune responses.

Keywords: antiviral; cancer; immunomodulatory; tetherin.

FIG. 1.

BST-2 regulation of the IFN-I response. (1) Virion interacts with cell surface receptors to enter the cell. (2) Viral genome (RNA) is recognized by the RLRs. RIG-I signals are transduced to the transcription factors through stimulation of MAVS at the mitochondrion-associated membrane. Activation of MAVS leads to phosphorylation of IRF3. Phosphorylated dimers of IRF3 then translocate to the nucleus where they bind and activate specific promoters triggering expression of IFNs. (3) Type-I IFNs interact with IFNAR, recruit, and phosphorylate the STAT1 and STAT2. STAT1 and STAT2 form a heterodimer that, in turn, recruits the IRF9 to make a complex. This complex translocates to the nucleus and induces expression of genes (e.g., BST-2) regulated by IFN-stimulated response elements. (4) BST-2 recruits the E3 ubiquitin ligase MARCH 8. (5) MARCH 8 then catalyzes the K27-linked polyubiquitin chains on MAVS at K7 position. (6) Cargo receptor NDP52 recognizes ubiquitinated MAVS. (7) NDP52 delivers MAVS to autophagosome for degradation. (8) BST-2-mediated autosomal degradation of MAVS and terminal of RIG-I, MAVS-mediated IFNI production via a negative feedback manner. BST-2, bone marrow stromal antigen 2; IFN, interferon; IRF3, IFN response factor 3; IFNAR, IFN-α/β receptor; MAVS, mitochondrial antiviral-signaling protein; RLR, RIG-1–like receptor; STAT, signal transducers and activators of transcription.

FIG. 2.

Antiviral and immunomodulatory functions of BST-2. (A) (1) BST-2 interacts with viral envelope and restricts cellular egress of nascent virion that, in turn, internalizes the virion through endocytosis. (2) In addition, endosomally expressed BST-2 halts virion trafficking and likely allows more time for endosomal proteases to act upon and degrade the virions. (3) Endosomal degradation of viral envelope facilitates release of genomic RNA that activates TLR3 and TLR7-mediated innate immune pathways. (4, 5) Activation of TLR3 and TLR7 along with other costimulatory molecules can further enhance expression of ISGs and cytokines in antigen presenting cells. (6) Cytokines such as IL-15 can promote NK cell activation and function. (7) Proteolytically degraded viral proteins generate a plethora of viral peptides that are often cross-presented by MHC I and can stimulate CD8 T cells. (8) Similarly, peptides loaded into MHC II can promote CD4 T cell activation. (B) In HIV-I–infected cells, the interaction between BST-2 and viral Env protein can increase accumulation of Env at the surface of the cell. This can facilitate interactions with circulating antibodies against HIV-1 and stimulate ADCC-mediated elimination of the infected cell. (C) BST-2 can tether exosomes like viral envelopes restricting their movement. Exosomes often carry signaling molecules such as DAMPs and activated EGFR. DAMP-carrying exosomes can activate antiviral immunity, whereas EGFR-carrying exosomes can suppress it. ADCC, antibody-dependent cellular cytotoxicity; DAMPs, damage-associated molecular patterns; EGFR, epidermal growth factor receptor; HIV-1, human immunodeficiency virus-1; IL, interleukin; ISGs, IFN-stimulated genes; TLR, Toll-like receptor.

FIG. 3.

The influence of BST-2 on tumor cell survival, invasion, and migration. (A) The dimeric form of BST-2 can facilitate cell-to-cell interactions or extracellular matrix interactions. BST-2 activation leads to phosphorylation of its cytoplasmic tail (most likely in the tyrosine-6 and tyrosine-8 positions). Phosphorylated BST-2 recruits GRB-2 and activates a kinase (unknown) that phosphorylates ERK (pERK), which, in turn, phosphorylates BIM, resulting in subsequent proteasomal degradation of BIM. In the absence of BIM, procaspase-3 is neither cleaved nor activated. This results in cancer cell survival. In a monomeric form, cytoplasmic domain of BST-2 is not phosphorylated, which can promote apoptosis of cancer cells. (B) The YXY motif of BST-2 is responsible for cancer cell migration and invasion. In the absence of the YXY motif, cancer cells exhibit a reduced migration rate.