TRIM32

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.

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
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9q33.1 Start 116,687,302 bp[1] End 116,701,300 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 C1|4 34.43 cM Start 65,604,986 bp[2] End 65,616,238 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity • myosin binding • GO:0001105 transcription coactivator activity • zinc ion binding • Tat protein binding • metal ion binding • ubiquitin-protein transferase activity • protein self-association • ubiquitin binding • GO:0001948 protein binding • RNA binding • translation initiation factor binding • transferase activity • identical protein binding Cellular component • cytoplasm • cytosol • intracellular • striated muscle myosin thick filament • cell 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 sequence-specific 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 system • 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 • negative regulation of viral release from host cell • 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: 65.6 – 65.62 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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

1. GRCh38: Ensembl release 89: ENSG00000119401 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000051675 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (May 2001). "The tripartite motif family identifies cell compartments". EMBO J. 20 (9): 2140–51. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580.
6. Fridell RA, Harding LS, Bogerd HP, Cullen BR (Jul 1995). "Identification of a novel human zinc finger protein that specifically interacts with the activation domain of lentiviral Tat proteins". Virology. 209 (2): 347–57. doi:10.1006/viro.1995.1266. PMID 7778269.
7. Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA, Kim KY, Huang J, Elbedour K, Carmi R, Slusarski DC, Casavant TL, Stone EM, Sheffield VC (Apr 2006). "Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11)". Proc Natl Acad Sci U S A. 103 (16): 6287–92. doi:10.1073/pnas.0600158103. PMC 1458870. PMID 16606853.
8. "Entrez Gene: TRIM32 tripartite motif-containing 32".
9. Kudryashova E, Kudryashov D, Kramerova I, Spencer MJ (Nov 2005). "Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin". J Mol Biol. 354 (2): 413–24. doi:10.1016/j.jmb.2005.09.068. PMID 16243356.
10. Kano S, Miyajima N, Fukuda S, Hatakeyama S (July 2008). "Tripartite motif protein 32 facilitates cell growth and migration via degradation of Abl-interactor 2". Cancer Res. 68 (14): 5572–80. doi:10.1158/0008-5472.CAN-07-6231. PMID 18632609.
11. Schwamborn J, Berezikov E, Knoblich J (March 2009). "The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors". Cell. 136 (5): 913–925. doi:10.1016/j.cell.2008.12.024. PMC 2988196. PMID 19269368.
12. Locke M, Tinsley CL, Benson MA, Blake DJ (Apr 2009). "TRIM32 is an E3 ubiquitin ligase for dysbindin". Hum Mol Genet. 18 (13): 2344–58. doi:10.1093/hmg/ddp167. PMC 2694686. PMID 19349376.
13. Kudryashova E, Wu J, Havton LA, Spencer MJ (Apr 2009). "Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component". Hum Mol Genet. 18 (7): 1353–67. doi:10.1093/hmg/ddp036. PMC 2722196. PMID 19155210.
14. Albor A, El-Hizawi S, Horn EJ, Laederich M, Frosk P, Wrogemann K, Kulesz-Martin M (Jun 2006). "The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB". J Biol Chem. 281 (35): 25850–66. doi:10.1074/jbc.M601655200. PMID 16816390.
15. Hamosh, Ada (2012-11-02). "OMIM entry #209900 Bardet-Biedl Syndrome; BBS". Online Mendelian Inheritance in Man. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine. Retrieved 2013-09-04.

External links

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

Further reading

• Albor A, El-Hizawi S, Horn EJ, et al. (2006). "The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB". J. Biol. Chem. 281 (35): 25850–66. doi:10.1074/jbc.M601655200. PMID 16816390.
• Lim J, Hao T, Shaw C, et al. (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569.
• Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
• Schoser BG, Frosk P, Engel AG, et al. (2005). "Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H". Ann. Neurol. 57 (4): 591–5. doi:10.1002/ana.20441. PMID 15786463.
• Benzinger A, Muster N, Koch HB, et al. (2005). "Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer". Mol. Cell. Proteomics. 4 (6): 785–95. doi:10.1074/mcp.M500021-MCP200. PMID 15778465.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9". Nature. 429 (6990): 369–74. doi:10.1038/nature02465. PMC 2734081. PMID 15164053.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Frosk P, Weiler T, Nylen E, et al. (2002). "Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene". Am. J. Hum. Genet. 70 (3): 663–72. doi:10.1086/339083. PMC 447621. PMID 11822024.
• Weiler T, Greenberg CR, Zelinski T, et al. (1998). "A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus". Am. J. Hum. Genet. 63 (1): 140–7. doi:10.1086/301925. PMC 1377246. PMID 9634523.