TRIM32

TRIM32
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CT2, 5FEY
Identifiers
Aliases	TRIM32, BBS11, HT2A, LGMD2H, TATIP, tripartite motif containing 32, LGMDR8
External IDs	OMIM: 602290; MGI: 1917057; HomoloGene: 36327; GeneCards: TRIM32; OMA:TRIM32 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9q33.1 Start 116,687,305 bp[1] End 116,701,300 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 C1|4 34.43 cM Start 65,523,223 bp[2] End 65,534,475 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium tibialis anterior muscle gastrocnemius muscle secondary oocyte testicle muscle of thigh deltoid muscle gonad Skeletal muscle tissue of biceps brachii bronchial epithelial cell Top expressed in dorsomedial hypothalamic nucleus piriform cortex habenula ventral tegmental area superior colliculus subiculum visual cortex dorsal tegmental nucleus medial geniculate nucleus lobe of cerebellum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ubiquitin protein ligase activity myosin binding transcription coactivator activity zinc ion binding Tat protein binding metal ion binding ubiquitin-protein transferase activity protein self-association ubiquitin binding protein binding RNA binding translation initiation factor binding transferase activity identical protein binding Cellular component cytoplasm cytosol intracellular anatomical structure striated muscle myosin thick filament nucleus Biological process positive regulation of interleukin-17-mediated signaling pathway axon development positive regulation of cell motility positive regulation of protein catabolic process muscle cell cellular homeostasis positive regulation of tumor necrosis factor-mediated signaling pathway positive regulation of cell migration positive regulation of DNA-binding transcription factor activity protein polyubiquitination negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage actin ubiquitination regulation of type I interferon production response to tumor necrosis factor positive regulation of neurogenesis positive regulation of cell growth positive regulation of cell cycle positive regulation of NF-kappaB transcription factor activity protein ubiquitination positive regulation of neuron differentiation tissue homeostasis positive regulation of striated muscle cell differentiation positive regulation of proteolysis positive regulation of I-kappaB kinase/NF-kappaB signaling innate immune response negative regulation of fibroblast proliferation positive regulation of chemokine (C-C motif) ligand 20 production fat cell differentiation response to UV negative regulation of viral transcription ubiquitin-dependent protein catabolic process positive regulation of nucleic acid-templated transcription protein K48-linked ubiquitination Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 22954 69807 Ensembl ENSG00000119401 ENSMUSG00000051675 UniProt Q13049 Q8CH72 RefSeq (mRNA) NM_001099679 NM_012210 NM_001379048 NM_001379049 NM_001379050 NM_001161782 NM_053084 RefSeq (protein) NP_001093149 NP_036342 NP_001365977 NP_001365978 NP_001365979 NP_001155254 NP_444314 Location (UCSC) Chr 9: 116.69 – 116.7 Mb Chr 4: 65.52 – 65.53 Mb PubMed search [3] [4]
Wikidata
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Tripartite motif-containing protein 32 is a protein that in humans is encoded by the TRIM32 gene.^[5][6][7][8] Since its discovery in 1995, TRIM32 has been shown to be implicated in a number of diverse biological pathways.

Structure

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region.^[8]

Subcellular distribution

The protein localizes to cytoplasmic bodies. The protein has also been localized to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein. The Tat protein activates transcription of HIV-1 genes.^[8]

Interactions

TRIM32 has been shown to interact with:

• actin,^[9]
• ABI2^[10]
• c-Myc,^[11]
• dysbindin,^[12] and
• piasy,^[13]

Function

Mechanism

Currently, TRIM32 is believed to employ two different mechanisms to affect molecular targets. First, it can act through its N-terminal RING finger as an E3 ubiquitin ligase, responsible for attaching ubiquitin molecules to lysine residues of target proteins, in order to mark them for proteosome degradation. Currently evidence suggests TRIM32 ubiquitinates multiple proteins including c-Myc, dysbindin, actin, piasy, and Abl-interactor2 (ABI2). The second mechanism by which TRIM32 is believed to operate involves binding of proteins to the C-terminal NHL repeat, which has been shown to activate miRNAs.^[11]

Development

Research has recently shown the importance of TRIM32 in the development of the mouse neocortex. In the mouse neocortex, neural progenitor cells generate daughter cells which either differentiate into specific neurons or maintain the progenitor state of the mother cell. TRIM32 helps control the balance between differentiating and progenitor cells by localizing to a pole during progenitor cell division, and thus becoming concentrated in one of the two daughter cells. This asymmetric division of TRIM32 induces neuronal differentiation in daughter cells which contain high TRIM32 concentrations, while cells with low TRIM32 concentrations retain progenitor cell fate. Proposed theories on how TRIM32 induces differentiation involve the ubiquitination of the transcription factor c-Myc and the binding of Argonaute-1 (Ago-1). The binding of Ago-1 induces activity of miRNAs, particularly Let-7a, which has been shown to play a role in regulating proliferation and neuronal differentiation.^[11]

Skeletal muscle

TRIM32 is expressed in skeletal muscle, where it interacts with myosin and may ubiquitinate actin (it has been shown to do so in vitro).^[9] No difference has been observed between wild-type and LHMD2H-mutated TRIM32 in terms of actin or myosin binding, however, and thus the mechanism which causes the muscular dystrophy, LGMD2H, is still unknown.^[14] Additionally, TRIM32 is known to ubiquitinate dysbindin, a protein associated with both skeletal muscles and neural tissue. The purpose and effects of the ubiquitination of dysbindin are as yet unclear.^[12]

Clinical significance

Mutation-associated diseases

Bardet–Biedl syndrome (BBS): TRIM32 is one of 14^[15] genes known to be linked with BBS. Specifically a mutation (P130S) in the B-box of TRIM32 gives rise to BBS.^[12]

Limb-girdle muscular dystrophy type2H (LGMD2H): LGMD2H is caused by 4 mutations of TRIM32 in the C-terminal NHL domain: D487N (third NHL repeat), R394H (first NHL repeat), T520TfsX13 (fourth NHL repeat), and D588del (fifth NHL repeat).^[12]

Cancer

TRIM32 is overexpressed in skin cancer cells. It is thought that TRIM32 regulates NF-κB activity through ubiquitination of Protein Inhibitor of Activated STAT Y (Piasy).^[13] Piasy acts as an inhibitor of NF-κB, and NF-κB acts as an anti-apoptotic factor. Thus, when Piasy is present, NF-κB is inhibited, and keratinocytes undergo apoptosis when exposed to ultraviolet-B radiation or TNFα, preventing cancer formation. When TRIM32 is overexpressed, Piasy is degraded, allowing NF-κB to function, and thus when cells are exposed to ultraviolet-B radiation or TNFα, apoptosis does not occur, potentially allowing cancer formation.^[14]

TRIM32 additionally promotes cancer formation by ubiquitinating Abl-interactor 2 (Abi2), which is a tumor suppressor and inhibitor of cell migration.^[13]

See also

• tripartite motif family

References

External links

• GeneReviews/NIH/NCBI/UW entry on Bardet-Biedl Syndrome

Further reading