Intracellular antibody‐mediated immunity and the role of TRIM21

McEwan, William A.; Mallery, Donna L.; Rhodes, David A.; Trowsdale, John; James, Leo C.

doi:10.1002/bies.201100093

Cited by 52 publications

(55 citation statements)

References 79 publications

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“…In the context of infection, virus with bound antibody, upon entering the cell cytoplasm, recruits TRIM21 via B30.2 (PRYSPRY) domain interaction. TRIM21-IgG binding coordinates complex immune responses, including pathogen restriction and innate immune signaling, in a mechanism termed antibody-dependent intracellular neutralization (ADIN) (45,46). the domain plays in the function of butyrophilins (36)(37)(38)(39).…”

Section: Tripartite Motif Molecules In Cell-autonomous Immunitymentioning

confidence: 99%

Regulation of Immunity by Butyrophilins

Rhodes

Reith

Trowsdale

2016

Annu. Rev. Immunol.

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132

137

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Butyrophilin molecules (commonly contracted to BTN), collectively take their name from the eponymous protein in cow's milk. They are considered to be members of the B7 family of costimulatory receptors, which includes B7.1 (CD80), B7.2 (CD86), and related molecules, such as PD-L1 (B7-H1, CD274), ICOS-L (CD275), and B7-H3 (CD276). These coreceptors modulate T cell responses upon antigen presentation by major histocompatibility complex and cognate αβ T cell receptor engagement. Molecules such as BTN3A1 (CD277), myelin oligodendrocyte glycoprotein, and mouse Skint1 and Btnl2, all members of the butyrophilin family, show greater structural and functional diversity than the canonical B7 receptors. Some butyrophilins mediate complex interactions between antigen-presenting cells and conventional αβ T cells, and others regulate the immune responses of specific γδ T cell subsets by mechanisms that have characteristics of both innate and adaptive immunity.

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Section: Tripartite Motif Molecules In Cell-autonomous Immunitymentioning

confidence: 99%

Regulation of Immunity by Butyrophilins

Rhodes

Reith

Trowsdale

2016

Annu. Rev. Immunol.

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132

137

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“…TRIM21, a cytosolic antibody receptor of ultrahigh affinity to IgG Fc (1,2), is recruited to antibody-bound virus and targets the complex to the proteasome for degradation (3). This process potently neutralizes viral infection and has been termed antibody-dependent intracellular neutralization (ADIN) (4). ADIN is dependent upon the E3 ubiquitin ligase activity of TRIM21 and can be abrogated by chemical inhibition of the proteasome.…”

Section: Intracellular Immunity | Cdc48mentioning

confidence: 99%

AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

Hauler

Mallery

McEwan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tripartite motif-containing 21 (TRIM21) is a cytosolic IgG receptor that mediates intracellular virus neutralization by antibody. TRIM21 targets virions for destruction in the proteasome, but it is unclear how a substrate as large as a viral capsid is degraded. Here, we identify the ATPase p97/valosin-containing protein (VCP), an enzyme with segregase and unfoldase activity, as a key player in this process. Depletion or catalytic inhibition of VCP prevents capsid degradation and reduces neutralization. VCP is required concurrently with the proteasome, as addition of inhibitor after proteasomal degradation has no effect. Moreover, our results suggest that it is the challenging nature of virus as a substrate that necessitates involvement of VCP, since intracellularly expressed IgG Fc is degraded in a VCP-independent manner. These results implicate VCP as an important host factor in antiviral immunity.A ntibody neutralization is a key component of the antiviral response and provides protective immunity. Our recent work has shown that neutralization can occur inside cells, in an effector-driven process mediated by tripartite motif-containing 21 (TRIM21). TRIM21, a cytosolic antibody receptor of ultrahigh affinity to IgG Fc (1, 2), is recruited to antibody-bound virus and targets the complex to the proteasome for degradation (3). This process potently neutralizes viral infection and has been termed antibody-dependent intracellular neutralization (ADIN) (4). ADIN is dependent upon the E3 ubiquitin ligase activity of TRIM21 and can be abrogated by chemical inhibition of the proteasome.Although both proteasomal activity and ubiquitination are necessary for ADIN, the exact mechanism of virus degradation is poorly understood. Specifically, it is not clear how the proteasome can degrade a virion, a compact proteinaceous particle much larger than the proteasome itself. The 26S proteasome has a mass of ∼2.5 MDa (5), and the pore through which substrates must pass to access the proteolytic chamber is no greater than 2 nm in diameter (6, 7). In contrast, human adenovirus (AdV), a virus potently neutralized by TRIM21, has a diameter of ∼100 nm and a mass of 150 MDa (8).Although there are ATPases in the 19S regulatory subunit of the 26S proteasome that may unfold substrates and allow them to enter through the pore (5, 6), AdV virions are much larger than any of the proteasome's known cellular substrates. Because ADIN has been shown to be independent of autophagy but dependent on proteasomal degradation (3), we hypothesized that an additional energydependent step of AdV capsid disassembly and/or unfolding might precede proteasomal degradation of the virus.In recent studies, the ATPase p97/VCP of the AAA (ATPases associated with diverse cellular activities) family has been implicated in the proteasomal degradation of certain cytosolic substrates (9-13). VCP is capable of dissociating proteins from large cellular structures such as the endoplasmic reticulum (14), the mitotic spindle (12), the nuclear envelope (15), and chromatin (1...

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“…69,70 The TRIM21 B30.2 domain has been shown to interact with interferon regulatory factors (IRF) 3 and 7 in a phosphorylation-dependent manner, targeting them for polyubiquitination and proteasomal degradation, thereby limiting the production of type I interferon following viral infection. 33 55 further add to growing evidence that the PRY region contributes key residues in interactions with target proteins.…”

Section: Spry/b302 Domain-containing Proteins Involved In Innate Celmentioning

confidence: 99%

Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity

et al. 2012

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The SPRY domain is a protein interaction module found in 77 murine and 100 human proteins, and is implicated in important biological pathways, including those that regulate innate and adaptive immunity. The current definition of the SPRY domain is based on a sequence repeat discovered in the splA kinase and ryanodine receptors. The greater SPRY family is divided into the B30.2 (which contains a PRY extension at the N-terminus) and ''SPRY-only'' sub-families. In this brief review, we examine the current structural and biochemical literature on SPRY/B30.2 domain involvement in key immune processes and highlight a PRY-like 60 amino acid region in the N-terminus of ''SPRY-only'' proteins. Phylogenetic, structural, and functional analyses suggest that this N-terminal region is related to the PRY region of B30.2 and should be characterized as part of an extended SPRY domain. Greater understanding of the functional importance of the N-terminal region in ''SPRY only'' proteins will enhance our ability to interrogate SPRY interactions with their respective binding partners.Keywords: SPRY domain; PRY; B30.2 domain; TRIM; BTN; SPSB; SOCS box; IgG; innate immunity; structure/function Abbreviations: Ash2L, ash2 (absent, small, or homeotic)-like; BTN, butyrophilin; DDX1, DEAD (Asp-Glu-Ala-Asp) box helicase 1; hnRNP, heterogeneous nuclear ribonucleoprotein; iNOS, inducible nitric oxide synthase; MID1, midline 1; RIG-I, retinoic acid-inducible gene I; HIV, human immunodeficiency virus; MEFV, Mediterranean fever; MLV, murine leukemia virus; NMR, nuclear magnetic resonance; IRF, interferon regulatory factor; NFjB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; NO, nitric oxide; FMF, familial Mediterranean fever; Fbxo45, F-box protein 45; IgG, immunoglobulin G; PYD, pyrin domain; RNF135, ring finger protein 135; Rbx2, RING box protein 2; RyR, ryanodine receptor; RING, really interesting new gene; RBCC, RING/B-box/coiled coil; SPRY, in splA kinase and ryanodine receptor; SOCS, suppressor of cytokine signaling; SPSB, SPRY domain-containing SOCS box; TRIM, tripartite motif; TLRs, toll-like receptors.

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Intracellular antibody‐mediated immunity and the role of TRIM21

Cited by 52 publications

References 79 publications

Regulation of Immunity by Butyrophilins

Regulation of Immunity by Butyrophilins

AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity

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