TRIM family proteins and their emerging roles in innate immunity

Abstract

The superfamily of tripartite motif-containing (TRIM) proteins is conserved throughout the metazoan kingdom and has expanded rapidly during vertebrate evolution; there are now more than 60 TRIM proteins known in humans and mice. Many TRIM proteins are induced by type I and type II interferons, which are crucial for many aspects of resistance to pathogens, and several are known to be required for the restriction of infection by lentiviruses. In this Review, we describe recent data that reveal broader antiviral and antimicrobial activities of TRIM proteins and discuss their involvement in the regulation of pathogen-recognition and transcriptional pathways in host defence.

Figure 1. Effects of human and mouse TRIM proteins on infection with HIV

Stages in the life cycle of HIV, from cell binding and fusion to release from the cell^,,,, are depicted on the left. Human tripartite motif-containing (TRIM) family members that are known to inhibit specific stages of the cycle are shown alongside. TRIM family members that are known to affect viral entry, viral gene expression or viral release, but for which the exact stage affected is not known, are shown on the right. Here, the definition of viral entry includes events from binding and fusion of the virus to its cellular receptors to the expression of viral proteins. Viral release relates to the presence of infectious virus or virus-encoded proteins in the supernatant of cultured infected cells^,. The TRIM proteins that affect gene expression include those that might affect viral transcription or translation from the integrated provirus. Proteins with moderate inhibitory or promoting effects are listed in parentheses. PML, promyelocytic leukaemia.

Figure 2. TRIM proteins in IFN signalling

Interferon-γ (IFNγ) and type I IFNs (IFNα and IFNβ) activate STAT1 (signal transducer and activator of transcription 1) and the STAT–IRF9 (IFN-regulatory factor 9) complex, respectively, which leads to the induction of transcription of many tripartite motif-containing (TRIM) genes^, (see also TABLE 2). TRIM8 activation, which is induced by IFNγ and STAT1, blocks suppressor of cytokine signalling 1 (SOCS1), a negative regulator of IFNγ signalling. TRIM21, which is activated by IFNs, interacts with IFN-induced IRF8, which leads to its ubiquitylation. Ubiquitylated IRF8 then increases transcription from the promoter of IL12p40 (interleukin-12, p40 subunit) and presumably increases the transcription of other target genes, including PML (promyelocytic leukaemia). IRF8 is also ubiquitylated by Casitas B-lineage lymphoma (CBL), which leads to proteasome-mediated degradation. IFNAR, IFNα receptor; IFNGR, IFNγ receptor; JAK, Janus kinase; TYK2, tyrosine kinase 2; Ub, ubiquitin.

Figure 3. TRIM proteins in TLR, RIG-I and MDA5 signalling pathways

Following engagement by ligand, Toll-like receptors (TLRs) that are expressed on the cell surface (TLR2, TLR4 and TLR5) and on endosomes (TLR3, TLR7, TLR8 and TLR9) activate downstream signalling pathways that lead to the activation of nuclear factor-κB (NF-κB), interferon (IFN)-regulatory factor 3 (IRF3) and IRF7. This induces the expression of type I IFNs and pro-inflammatory cytokines, such as tumour-necrosis factor (TNF), interleukin-1 (IL-1) and IL-6. Binding of double-stranded RNA or 5′ phosphorylated single-stranded RNA by the RNA helicases retinoic-acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), respectively, also activates the two pathways. Tripartite motif-containing protein 30α (TRIM30α) binds to TAK1 (transforming growth factor-β (TGFβ)-activated kinase 1) and destabilizes TAK1-binding protein 2 (TAB2) and TAB3 to inhibit NF-κB activation. TRIM27 binds to IκB (inhibitor of NF-κB) kinases (IKKs) and blocks the activation of NF-κB and of IRF3 and IRF7 (REF. 100). TRIM25 binds to RIG-I to conjugate ubiquitin, thereby promoting the activation of downstream pathways to increase cytokine induction. IPS1, IFNB-promoter stimulator 1; IRAK, IL-1-receptor-associated kinase; MAL, myeloid differentiation primary-response gene 88 (MyD88)-adaptor-like protein; TBK1, TNF-receptor-associated factor (TRAF)-family-member-associated NF-κB activator (TANK)-binding kinase 1; TRAM, Toll/IL-1-receptor-domain-containing adaptor protein inducing IFNβ (TRIF)-related adaptor molecule; Ub, ubiquitin.