Alt. symbols: C20orf18 | RBCK2 | XAP4 | RNF54 | ZRANB4 | UBCE7IP3 | HOIL1 | HOIL-1

Approved name: RANBP2-type and C3HC4-type zinc finger containing 1
Alt. names: chromosome 20 open reading frame 18, RanBP-type and C3HC4-type zinc finger containing 1 | heme-oxidized IRP2 ubiquitin ligase 1

Location: 20p13: 407498 - 432139 (+)
Gene type: protein_coding, 20 transcripts.

Scores: LoFtool: 0.524000 | pLI: 0.21209445 | LOEUF: 0.453

HGNC: 15864

NCBI: 10616, RefSeq: NG_033233.1

Ensembl: ENSG00000125826.22

LRG_728 | Status: public

OMIM: 610924

Expression | ProteinAtlas

LUBAC is a heterotrimeric E3 ligase complex (HOIP, HOIL-1 and SHARPIN) responsible for adding linear polyubiquitin chains to target proteins after receptor engagement and activation to stabilize various receptor signaling complexes associated with TNFR1, TLRs, IL-1R and CD40 (PMID: 21455181, 23104095, 28469620). LUBAC has been shown to be important for CD40-dependent activation of B cells in both humans and mice (PMID: 20614026, 21829693, 23942237, 23104095). Moreover, as a component of the NF-κB cascade, it targets key proteins such as NEMO and RIPK1 to play a key role in IKK complex activation. HOIP is the catalytically active component of LUBAC, but HOIL1 is required for LUBAC assembly, stability, and retention in the TNFR1 signaling complex to prevent aberrant cell death.

Germline mutations in two of three LUBAC subunits have now been identified and its disruption results in dysregulated immune responses, featuring both an inability to properly upregulate NF-κB activity in non-immune cells and hyperresponsiveness to IL-1β, along with excessive pro-inflammatory cytokine production, in immune cells such as monocytes (PMID: 32107482). Biallelic mutations in RBCK1, encoding HOIL1, were the first LUBAC deficiencies identified. This condition is now designate d Polyglucosan body myopathy 1 with or without immunodeficiency [OMIM: 615895]. Homozygous or compound heterozygous truncating RBCK1 mutations, leading to both HOIL1 and LUBAC complex LOF, have been identified in 3 patients with chronic autoinflammation, invasive bacterial infections and amylopectinosis of skeletal and cardiac muscle (PMID: 23104095). Notably, patient fibroblasts showed impaired NEMO/IKBKG recruitment to cytokine receptors, resulting in defective NF-κB activation with weak induction of TNF- and IL-1β-dependent genes, potentially explaining the immunodeficiency phenotype. In contrast, patient leukocyte gene expression profiles showed hyperactivation with enhanced IL-1β responses, consistent with the autoinflammation seen. In contrast to these largely N-terminal mutations, biallelic LOF mutations affecting the middle or C-terminal part of RBCK1 have been associated with early-onset polyglucosan body myopathy without evidence of severe immunodeficiency [OMIM: 615895] (PMID: 23798481). [Load More]