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.^[5][6][7] 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.^[8][9] Through its apoptotic function, GHITM may be involved in tumor metastasis and innate antiviral responses.^[10][11]

GHITM
Identifiers
Aliases	GHITM, DERP2, HSPC282, MICS1, PTD010, TMBIM5, My021, growth hormone inducible transmembrane protein
External IDs	MGI: 1913342; HomoloGene: 8667; GeneCards: GHITM; OMA:GHITM - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q23.1 Start 84,139,482 bp[1] End 84,154,841 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 B|14 21.29 cM Start 36,842,049 bp[2] End 36,857,229 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm right ventricle myocardium of left ventricle mucosa of ileum deltoid muscle tibialis anterior muscle mucosa of colon lateral nuclear group of thalamus mucosa of sigmoid colon Skeletal muscle tissue of rectus abdominis Top expressed in blood right kidney cerebellar cortex medial vestibular nucleus brown adipose tissue muscle of thigh pontine nuclei neural layer of retina superior frontal gyrus deep cerebellar nuclei More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding molecular function Cellular component extracellular exosome membrane integral component of membrane mitochondrial inner membrane mitochondrion Biological process apoptotic process biological process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 27069 66092 Ensembl ENSG00000165678 ENSMUSG00000041028 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 Mb Chr 14: 36.84 – 36.86 Mb PubMed search [3] [4]
Wikidata
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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.^[8][9][10] 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.^[9][10]

Function

GHITM is a mitochondrial protein and a member of the TMBIM family and BAX inhibitor-1 (BI1) superfamily.^[8][9] It is ubiquitously expressed but is especially abundant in the brain, heart, liver, kidney, and skeletal muscle and scarce in the intestines and thymus.^[9] 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.^[8][9] 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.^[9]

Clinical significance

GHITM may be involved in tumor metastasis through its interactions with the Bcl-2 family proteins to regulate apoptosis.^[10][11] Its role as an apoptotic regulator may also associate it with innate antiviral responses.^[11] Overexpression of GHITM has also been observed to speed up the ageing process in HIV infected patients.^[12]

Interactions

GHITM has been shown to interact with cytochrome c.^[8]