GHITM

Growth hormone-inducible transmembrane protein (GHITM), also known as transmembrane BAX inhibitor motif containing protein 5 (TMBIM5), is a protein that in humans is encoded by the GHITM gene on chromosome 10.[4][5][6] It is a member of the BAX inhibitor motif containing (TMBIM) family and localizes to the inner mitochondrial membrane (IMM), as well as the endoplasmic reticulum (ER), where it plays a role in apoptosis through mediating mitochondrial morphology and cytochrome c release.[7][8] Through its apoptotic function, GHITM may be involved in tumor metastasis and innate antiviral responses.[9][10]

GHITM
Identifiers
AliasesGHITM, DERP2, HSPC282, MICS1, PTD010, TMBIM5, My021, growth hormone inducible transmembrane protein
External IDsMGI: 1913342 HomoloGene: 8667 GeneCards: GHITM
Gene location (Human)
Chr.Chromosome 10 (human)[1]
Band10q23.1Start84,139,509 bp[1]
End84,153,568 bp[1]
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

27069

66092

Ensembl

ENSG00000165678

n/a

UniProt

Q9H3K2

Q91VC9

RefSeq (mRNA)

NM_014394

NM_001199122
NM_078478
NM_001359902

RefSeq (protein)

NP_055209

NP_001186051
NP_510963
NP_001346831

Location (UCSC)Chr 10: 84.14 – 84.15 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

This gene encodes a 37 kDa protein which putatively contains six to eight transmembrane domains. As a member of the TMBIM family, GHITM shares a transmembrane BAX inhibitor motif, a semi-hydrophobic transmembrane domain, and similar tertiary structure with the other five members. However, unlike the other members, GHITM possesses a unique acidic (D) instead of a basic (H or R) residue near its second transmembrane domain, as well as an additional transmembrane domain that, after cleavage behind residue 57 (SREY|A), signals for localization to the IMM.[7][8][9] Nonetheless, it is possible that cleavage at different sites (XXRR-like motif (LAAR) in the N-terminal and a KKXX-like motif (GNRK) in the C-terminal) or alternative splicing may account for the protein’s observed localization to the ER.[8][9]

Function

GHITM is a mitochondrial protein and a member of the TMBIM family and BAX inhibitor-1 (BI1) superfamily.[7][8] It is ubiquitously expressed but is especially abundant in the brain, heart, liver, kidney, and skeletal muscle and scarce in the intestines and thymus.[8] This protein localizes specifically to the IMM, where it regulates apoptosis through two separate processes: (1) the BAX-independent management of mitochondrial morphology and (2) the release of cytochrome c. In the first process, GHITM maintains cristae organization, and its downregulation results in mitochondrial fragmentation, possibly through inducing fusing of the cristae structures, thus leading to the release of proapoptotic proteins such as cytochrome c, Smac, and Htra2. Meanwhile, in the second process, GHITM is responsible for cross-linking cytochrome c to the IMM, and upregulation of GHITM is associated with delayed cytochrome c release, regardless of outer mitochondrial membrane permeabilization. Thus, GHITM controls the release of cytochrome c from the mitochondria and can potentially interfere with the apoptotic process to promote cell survival.[7][8] Moreover, GHITM may further plays a role in apoptosis through maintaining calcium ion homeostasis in the ER. However, while overexpression of the other TMBIM proteins exhibit antiapoptotic effects by decreasing calcium ion concentrations, and thus preventing mitochondrial calcium ion overload, depolarization, ATP loss, reactive oxygen species production, cytochrome c release, and ultimately, cell death, overexpression of GHITM produces the opposite effect.[8]

Clinical significance

GHITM may be involved in tumor metastasis through its interactions with the Bcl-2 family proteins to regulate apoptosis.[9][10] Its role as an apoptotic regulator may also associate it with innate antiviral responses.[10] Overexpression of GHITM has also been observed to speed up the ageing process in HIV infected patients.[11]

Interactions

GHITM has been shown to interact with cytochrome c.[7]

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References
  1. GRCh38: Ensembl release 89: ENSG00000165678 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
  5. Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
  6. "Entrez Gene: GHITM growth hormone inducible transmembrane protein".
  7. Oka T, Sayano T, Tamai S, Yokota S, Kato H, Fujii G, Mihara K (Jun 2008). "Identification of a novel protein MICS1 that is involved in maintenance of mitochondrial morphology and apoptotic release of cytochrome c". Molecular Biology of the Cell. 19 (6): 2597–608. doi:10.1091/mbc.E07-12-1205. PMC 2397309. PMID 18417609.
  8. Lisak DA, Schacht T, Enders V, Habicht J, Kiviluoto S, Schneider J, Henke N, Bultynck G, Methner A (Sep 2015). "The transmembrane Bax inhibitor motif (TMBIM) containing protein family: Tissue expression, intracellular localization and effects on the ER CA(2+)-filling state". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1853 (9): 2104–14. doi:10.1016/j.bbamcr.2015.03.002. PMID 25764978.
  9. Zhou J, Zhu T, Hu C, Li H, Chen G, Xu G, Wang S, Zhou J, Ma D (Jun 2008). "Comparative genomics and function analysis on BI1 family". Computational Biology and Chemistry. 32 (3): 159–62. doi:10.1016/j.compbiolchem.2008.01.002. PMID 18440869.
  10. Li S, Wang L, Berman M, Kong YY, Dorf ME (Sep 2011). "Mapping a dynamic innate immunity protein interaction network regulating type I interferon production". Immunity. 35 (3): 426–40. doi:10.1016/j.immuni.2011.06.014. PMC 3253658. PMID 21903422.
  11. Moni MA, Liò P (24 October 2014). "Network-based analysis of comorbidities risk during an infection: SARS and HIV case studies". BMC Bioinformatics. 15: 333. doi:10.1186/1471-2105-15-333. PMC 4363349. PMID 25344230.

Further reading
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