TRIM5alpha

Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene.^[5] The alpha isoform of this protein, TRIM5α, is a retrovirus restriction factor, which mediates a species-specific early block to retrovirus infection.

TRIM5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ECV, 2YRG
Identifiers
Aliases	TRIM5, RNF88, TRIM5alpha, tripartite motif containing 5
External IDs	OMIM: 608487; MGI: 4821183; HomoloGene: 75345; GeneCards: TRIM5; OMA:TRIM5 - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p15.4 Start 5,663,195 bp[1] End 5,938,619 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 E3 Start 103,987,961 bp[2] End 104,002,569 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sural nerve germinal epithelium palpebral conjunctiva stromal cell of endometrium body of pancreas seminal vesicula monocyte Descending thoracic aorta visceral pleura blood Top expressed in granulocyte thymus female urethra duodenum bone marrow aortic valve spleen ascending aorta esophagus mesenteric lymph nodes More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein-macromolecule adaptor activity protein homodimerization activity pattern recognition receptor activity zinc ion binding metal ion binding protein binding identical protein binding protein kinase binding transferase activity ubiquitin-protein transferase activity Cellular component cytoplasm cytosol omegasome intracellular anatomical structure nucleus P-body Biological process regulation of lipopolysaccharide-mediated signaling pathway interferon-gamma-mediated signaling pathway protein K63-linked ubiquitination immune system process protein trimerization positive regulation of DNA-binding transcription factor activity regulation of protein localization autophagy positive regulation of NF-kappaB transcription factor activity defense response to virus protein ubiquitination activation of innate immune response positive regulation of I-kappaB kinase/NF-kappaB signaling innate immune response viral process positive regulation of MAPK cascade pattern recognition receptor signaling pathway negative regulation of viral entry into host cell Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 85363 319236 Ensembl ENSG00000132256 ENSMUSG00000057143 UniProt Q9C035 D3Z3L3 RefSeq (mRNA) NM_033034 NM_033092 NM_033093 NM_001146007 NM_175677 RefSeq (protein) NP_149023 NP_149083 NP_149084 NP_001139479 NP_783608 Location (UCSC) Chr 11: 5.66 – 5.94 Mb Chr 7: 103.99 – 104 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

TRIM5α is composed of 493 amino acids which is found in the cells of most primates. TRIM5α is an intrinsic immune factor important in the innate immune defense against retroviruses, along with the APOBEC family of proteins,^[6][7] tetherin and TRIM22.

Structure

TRIM5α belongs to the TRIM protein family (TRIM stands for TRIpartite Motif); this family was first identified by Reddy in 1992 as a set of proteins which contain a RING type zinc finger domain, a B-box zinc binding domain, followed by a coiled-coil region.^[8] TRIM5α bears the C-terminal PRY-SPRY or B30.2 domain in addition to the other domains.

Function

TRIM5α is a cytosolic protein that recognizes specific motifs on incoming viral capsids. Upon recognition, TRIM5α assembles into a hexagonal lattice that coats the capsid surface in a highly regular, tessellated manner. Each hexagon in this lattice is formed by interactions between trimeric hub-and-spoke structures.^[9] This coating disrupts the normal uncoating process, thereby (1) blocking nuclear import of the viral genome and (2) interfering with reverse transcription of viral RNA into DNA, which is required for integration into the host genome and subsequent viral gene expression.^[10][11]

While the full mechanism remains incompletely understood, it is known that TRIM5α promotes proteasome-dependent degradation of capsid proteins from restricted viruses.^[12] This process involves the recruitment of ubiquitin by the TRIM5α lattice, which subsequently targets the capsid for degradation by the proteasome.^[9] Additional host proteins may participate in TRIM5α-mediated restriction, though definitive evidence is still lacking. One known cofactor is Cyclophilin A, which is required for TRIM5α-mediated HIV-1 inhibition in Old World monkey cells.^[13] The specificity of TRIM5α-mediated restriction—that is, which retroviruses are targeted—is determined by the amino acid sequence of its C-terminal domain, known as the B30.2 or PRY-SPRY domain.^[14] Within this domain, amino acid residue 332 plays a particularly important role in determining which retroviruses are restricted.^[15][16]

When a retrovirus enters the host cell cytosol, its capsid was once thought to undergo complete uncoating immediately. However, this model is now considered oversimplified. Current understanding suggests that uncoating is a progressive process that begins in the cytosol and continues as the capsid approaches the nucleus, with final disassembly typically—but not always—occurring within the nucleus.^[17] Reverse transcription of the viral genome also occurs within the intact or partially uncoated capsid, producing viral DNA necessary for the formation of daughter virions.^[18]

Clinical significance

PtERV1 resistance

TRIM5α may have played a critical role in the human immune defense system about 4 million years ago, when the retrovirus PtERV1 was infecting the ancestors of modern chimpanzees.^[16] While no trace of PtERV1 has yet been found in the human genome, about 130 traces of PtERV1 DNA have been found in the genome of modern chimpanzees. After recreating part of the PtERV1 retrovirus, it was reported that TRIM5α prevents the virus from entering human cells in vitro. While this cellular defense mechanism may have been very useful 4 million years ago when facing a PtERV1 epidemic, it has the side effect of leaving cells more susceptible to attack by the HIV-1 retrovirus. Recently, doubt has been cast over these conclusions. By using a PtERV1 capsid, which produces higher titer virus-like particles, Perez-Caballero et al. reported that PtERV1 is not restricted by either human or chimpanzee TRIM5α.^[19]

HIV-1 resistance

Rhesus macaques, a species of Old World monkeys, are almost completely resistant to HIV-1, the virus that causes AIDS in humans.^[20] This resistance is due to a version of the antiviral protein TRIM5α that binds the HIV-1 capsid with high affinity and rapidly induces its degradation, effectively neutralizing the virus.

Humans also express TRIM5α, but the human variant is not sufficiently adapted to block HIV-1 effectively. However, it can restrict other retroviruses, including certain strains of murine leukemia virus (MLV)^[21][22] and equine infectious anemia virus (EIAV).^[23][24] Before TRIM5α was identified as the underlying restriction factor, this antiviral activity had been observed and termed Ref1 in human cells and Lv1 in monkey cells. These terms are now largely obsolete.

A related protein, known as TRIMCyp (or TRIM5-CypA), was discovered in the owl monkey, a species of New World monkey. This fusion protein potently inhibits HIV-1 infection.^[25] A similar TRIMCyp protein has independently evolved in several species of Old World monkeys, including various macaques.^[26][27]

More recently, it has been shown that stimulation with interferon-α can activate the immunoproteasome, enabling human TRIM5α to effectively block HIV-1 by interfering with capsid-dependent DNA synthesis and infection.^[28]