TRIM14

Tripartite motif-containing 14 is a protein encoded by the TRIM14 gene in the human genome. It belongs to the TRIM family of proteins which contain the TRIM motif on the N-terminus. TRIM14 lacks the RING domain within the motif and therefore it loses the function of E3 ubiquitin ligase in eukaryotic cells. Instead, the PRYSPRY domain on the C-terminus allows TRIM14 to be categorized into an evolutionarily younger group of TRIM proteins which are involved in the regulation of innate immunity.[1] TRIM 14 is localized in both the cytoplasm and the cell nucleus.[2]

Function

TRIM14 acts in cell proliferation, differentiation, morphogenesis, autophagy and in the initiation of the anti-viral immune response by innate immunity.[3][4][5]

Overexpression of TRIM14 in mouse embryonic stem cells (mESC) leads to upregulation of several genes (hsp90ab1, prr13, pu.1, tnfrsf13c (baff-r), tnfrsf13b (taci), hlx1, hbp1, junb and pdgfrb) which are involved in early stage differentiation of embryonic stem cells, in the mesodermal layer. The same genes are upregulated in human embryonic kidney cells 293 (HEK293) (except for hlx1, hbp1, junb and pdgfrb). Therefore, TRIM14 regulates gene expression in different cell types by a universal mechanism: interaction with the transcription factors common to TRIM proteins.[5][6] The mouse homologue of TRIM14, the "Pub protein", was shown to interact with transcription factor PU.1 (SPI1) and inhibit its activity.[7] PU.1 is a transcription factor critical for proliferation and differentiation of myeloid cells and B lymphocytes.[8][9] Hence, TRIM14 (Pub) is likely associated with the regulation of development of the immune cells.

TRIM14 transfected HEK293 cell show increased transcription of eighteen genes involved in the innate immune system. They are ifna, il6 (ifnb2), isg15, raf-1, NF-kB (nf-kb1, rela, nf-kb2, relb), grb2, grb3-3, traf3ip2, junB, c-myb, pu.1, akt1, tyk2, erk2, and mek2. In the same cells, the stable expression of TRIM14 allowed the suppression of the replication of Sindbis virus.[3] The influence of TRIM14 on RNA viruses replication was proven in several experiments [10][11][12][13] and it was found to be upregulated in viral-infected tissues.[13][14][15] Additionally, TRIM14 knockout mice are lethal after herpes simplex virus (HSV) infection.[4]

The antiviral role of TRIM14 has also been confirmed by the inhibition of the selective autophagic degradation of the cytoplasmic DNA sensor, cGAS. In normal cells, cGAS is modified by the K48-polyubiquitin chain. It goes to the p62 mediated autophagic degradation and the type I IFN signalling is suppressed. Induction of TRIM14 by type I IFN leads to activation of USP14 which then cleaves the polyubiquitin chain from cGAS and type I IFN signalling is stabilized. So, there is a positive loop between TRIM14 and type I IFN signalling.[4]

Expression pattern

The mRNA for TRIM14 has been found in many organs with a prevalence in those organs with a high number of immune cells such as the spleen, lymph nodes, and gastrointestinal tract.[16]

References
  1. Sardiello, Marco; Cairo, Stefano; Fontanella, Bianca; Ballabio, Andrea; Meroni, Germana (2008-01-01). "Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties". BMC Evolutionary Biology. 8: 225. doi:10.1186/1471-2148-8-225. ISSN 1471-2148. PMC 2533329. PMID 18673550.
  2. Database, GeneCards Human Gene. "TRIM14 Gene - GeneCards | TRI14 Protein | TRI14 Antibody". www.genecards.org. Retrieved 2017-01-27.
  3. Nenasheva, V. V.; Kovaleva, G. V.; Uryvaev, L. V.; Ionova, K. S.; Dedova, A. V.; Vorkunova, G. K.; Chernyshenko, S. V.; Khaidarova, N. V.; Tarantul, V. Z. (2015-05-07). "Enhanced expression of trim14 gene suppressed Sindbis virus reproduction and modulated the transcription of a large number of genes of innate immunity". Immunologic Research. 62 (3): 255–262. doi:10.1007/s12026-015-8653-1. ISSN 0257-277X. PMID 25948474.
  4. Chen, Meixin; Meng, Qingcai; Qin, Yunfei; Liang, Puping; Tan, Peng; He, Lian; Zhou, Yubin; Chen, Yongjun; Huang, Junjiu (2016). "TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses". Molecular Cell. 64 (1): 105–119. doi:10.1016/j.molcel.2016.08.025. PMID 27666593.
  5. Nenasheva, Valentina V.; Kovaleva, Galina V.; Khaidarova, Nella V.; Novosadova, Ekaterina V.; Manuilova, Ekaterina S.; Antonov, Stanislav A.; Tarantul, Vyacheslav Z. (2013-10-03). "Trim14 overexpression causes the same transcriptional changes in mouse embryonic stem cells and human HEK293 cells". In Vitro Cellular & Developmental Biology - Animal. 50 (2): 121–128. doi:10.1007/s11626-013-9683-4. ISSN 1071-2690. PMID 24092016.
  6. Herquel, Benjamin; Ouararhni, Khalid; Khetchoumian, Konstantin; Ignat, Mihaela; Teletin, Marius; Mark, Manuel; Béchade, Guillaume; Dorsselaer, Alain Van; Sanglier-Cianférani, Sarah (2011-05-17). "Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma". Proceedings of the National Academy of Sciences. 108 (20): 8212–8217. Bibcode:2011PNAS..108.8212H. doi:10.1073/pnas.1101544108. ISSN 0027-8424. PMC 3100982. PMID 21531907.
  7. Hirose, Satoshi; Nishizumi, Hirofumi; Sakano, Hitoshi (2003-11-14). "Pub, a novel PU.1 binding protein, regulates the transcriptional activity of PU.1". Biochemical and Biophysical Research Communications. 311 (2): 351–360. doi:10.1016/j.bbrc.2003.09.212. ISSN 0006-291X. PMID 14592421.
  8. Fisher, Robert C.; Scott, Edward W. (1998-01-01). "Role of PU.1 in Hematopoiesis". Stem Cells. 16 (1): 25–37. doi:10.1002/stem.160025. ISSN 1549-4918. PMID 9474745.
  9. Lloberas, J.; Soler, C.; Celada, A. (1999-04-01). "The key role of PU.1/SPI-1 in B cells, myeloid cells and macrophages". Immunology Today. 20 (4): 184–189. doi:10.1016/S0167-5699(99)01442-5. ISSN 0167-5699. PMID 10203717.
  10. Uchil, Pradeep D.; Quinlan, Brian D.; Chan, Wai-Tsing; Luna, Joseph M.; Mothes, Walther (2008-02-01). "TRIM E3 Ligases Interfere with Early and Late Stages of the Retroviral Life Cycle". PLOS Pathogens. 4 (2): e16. doi:10.1371/journal.ppat.0040016. ISSN 1553-7374. PMC 2222954. PMID 18248090.
  11. Uchil, Pradeep D.; Hinz, Angelika; Siegel, Steven; Coenen-Stass, Anna; Pertel, Thomas; Luban, Jeremy; Mothes, Walther (2013-01-01). "TRIM Protein-Mediated Regulation of Inflammatory and Innate Immune Signaling and Its Association with Antiretroviral Activity". Journal of Virology. 87 (1): 257–272. doi:10.1128/JVI.01804-12. ISSN 0022-538X. PMC 3536418. PMID 23077300.
  12. Zhou, Zhuo; Jia, Xue; Xue, Qinghua; Dou, Zhixun; Ma, Yijie; Zhao, Zhendong; Jiang, Zhengfan; He, Bin; Jin, Qi (2014-01-14). "TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response". Proceedings of the National Academy of Sciences. 111 (2): E245–E254. Bibcode:2014PNAS..111E.245Z. doi:10.1073/pnas.1316941111. ISSN 0027-8424. PMC 3896185. PMID 24379373.
  13. Wieland, Stefan; Thimme, Robert; Purcell, Robert H.; Chisari, Francis V. (2004-04-27). "Genomic analysis of the host response to hepatitis B virus infection". Proceedings of the National Academy of Sciences of the United States of America. 101 (17): 6669–6674. Bibcode:2004PNAS..101.6669W. doi:10.1073/pnas.0401771101. ISSN 0027-8424. PMC 404103. PMID 15100412.
  14. Chen, Yin; Hamati, Edward; Lee, Pak-Kei; Lee, Wai-Ming; Wachi, Shinichiro; Schnurr, David; Yagi, Shigeo; Dolganov, Gregory; Boushey, Homer (2006-02-01). "Rhinovirus Induces Airway Epithelial Gene Expression through Double-Stranded RNA and IFN-Dependent Pathways". American Journal of Respiratory Cell and Molecular Biology. 34 (2): 192–203. doi:10.1165/rcmb.2004-0417OC. ISSN 1044-1549. PMC 2644182. PMID 16210696.
  15. Ramilo, Octavio; Allman, Windy; Chung, Wendy; Mejias, Asuncion; Ardura, Monica; Glaser, Casey; Wittkowski, Knut M.; Piqueras, Bernard; Banchereau, Jacques (2007-03-01). "Gene expression patterns in blood leukocytes discriminate patients with acute infections". Blood. 109 (5): 2066–2077. doi:10.1182/blood-2006-02-002477. ISSN 0006-4971. PMC 1801073. PMID 17105821.
  16. "Tissue expression of TRIM14 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-01-27.
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