Alt. symbols: IRF-2BP2

Approved name: interferon regulatory factor 2 binding protein 2
Alt. names: interferon regulatory factor 2binding protein 2 | IRF2binding protein 2

Location: 1q42.3: 234602300 - 234610178 (-)
Gene type: protein_coding, 3 transcripts.

Scores: LoFtool: | pLI: 0.47029132 | LOEUF: 0.451

HGNC: 21729

NCBI: 359948, RefSeq: .0

Ensembl: ENSG00000168264.12

LRG_ | Status: none

OMIM: 615332

Expression | ProteinAtlas

IRF2BP2 is an interferon regulatory factor-2 (IRF2) binding protein that has emerged as an important new transcriptional cofactor in the regulation of diverse processes such as apoptosis, survival, and cellular differentiation. It is thought to exert at least some of its effects in an IRF2-dependent manner and via its C-terminal transcriptional repression domain. In vitro studies have found that IRF2BP2 represses the NFAT1-dependent transactivation of NFAT-responsive promoters (PMID: 21576369), while acting as a coactivator of VEGFA expression in cardiac and skeletal muscle cells (PMID: 20702774). As such, IRF2BP2 dysregulation has been implicated in cancer development. IRF2BP2 is also implicated in both innate and adaptive immunity, via roles in macrophage regulation and lymphocyte activation. In terms of the latter, there is accumulating evidence for an important role of IRF2BP2 in B cell development, function and/or survival, as both gain-of-function (GOF) and loss-of-function (LOF) variants in human patients appear to cause humoral abnormalities (PMID: 27016798, 33864888, 34451894).

Both monoallelic gain-of-function (GOF) and loss-of-function (LOF) germline IRF2BP2 mutations have been associated to disease. Keller et al. (2016) identified the first family with 3 members affected by CVID caused by a monoallelic missense variant (p.S551N) in the C-terminal RING domain, which is thought essential for the protein’s repressive effects on transcription (PMID: 27016798). This variant led to increased IRF2BP2 transcript and protein levels, consistent with a GOF mechanism. Nucleofec tion of healthy control B-cells with the mutant construct led to decreased plasmablast development relative to the wild-type construct, suggesting a role for IRF2BP2 in the development or survival of B cell populations. More recently, Palmroth et al. (2021) identified a heterozygous LOF variant (c.625_665del, p.Ala209Glnfs*31) predicted to result in a truncated 238-aa protein in 2 adult siblings with lymphoid abnormalities and chronic hidradenitis suppurativa (PMID: 34451894). Patient cells showed increased baseline protein levels and phosphorylation of STAT1, the latter of which markedly more elevated with stimulation. Moreover, IFNα- and IFNβ-induced STAT4 phosphorylation and IL-7-induced STAT5 phosphorylation levels were also elevated in the male index patient over controls. The authors went on to show by Nanostring assay that STAT1- and IFN-dependent gene expression was elevated, and that expression of a wild-type but not mutant IRF2BP2 construct could significantly suppress constitutive and cytokine-stimulated STAT1 transcriptional activity in HEK293T cells. Finally, Baxter et al. (2022) identified a rare de novo heterozygous truncating variant (c.1606insTTT, p.Q536delinsX) in a young girl with IPEX-like disease (PMID: 33864888). The authors observed that IRF2BP2 mRNA levels were stable, but did not comment on the levels or stability of the protein product. [Load More]