Alt. symbols: UNC93

Approved name: unc-93 homolog B1, TLR signaling regulator
Alt. names: unc93 (C. elegans) homolog B1, unc-93 homolog B1 (C. elegans)

Location: 11q13.2: 67991100 - 68004982 (-)
Gene type: protein_coding, 9 transcripts.

Scores: LoFtool: | pLI: 0.51383738 | LOEUF: 0.510

HGNC: 13481

NCBI: 81622, RefSeq: NG_007581.1

Ensembl: ENSG00000110057.9

LRG_123 | Status: public

OMIM: 608204

Expression | ProteinAtlas

UNC93B1 encodes a membrane-spanning endoplasmic reticulum (ER) protein that plays an important role in innate and adaptive immunity by regulating nucleic acid-sensing Toll-like receptor (TLR) signaling. It is required for the transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the ER to endolysosomes where they can engage pathogen nucleotides and activate signaling cascades. Isnardi et al. (2008) suggested that it may play a role in the removal of autoreactive B-cells since UNC-93B-deficient patients showed defects in the establishment of B cell tolerance (PMID: 19006693). More recently, Majer et al. (2019) showed that it specifically limits signaling through TLR7 and prevents TLR7-dependent autoimmunity in mice (PMID: 31546246).

Casrouge et al. (2006) reported homozygosity for a 4-bp deletion or missense mutation (G261S) in patients with susceptibility to acute herpesviral encephalitis (PMID: 16973841). Patients had impaired type I IFN responses to HSV-1 and 10 other viruses but no other history of unusual infections and effectively controlled infections by at least 9 other viruses. Their PBMCs produced normal levels of IFN-gamma, TNF-alpha, IL-1beta, and IL-6. Lafaille et al. (2012) showed that HSE pathogenesis involve s nonhematopoietic CNS-resident cells by deriving iPSCs from the dermal fibroblasts of UNC93B1-deficient patients and controls and differentiating them into neural stem cells (NSCs), neurons, astrocytes, and oligodendrocytes (PMID: 23103873). Type I IFN induction in response to stimulation by poly(I:C) was dependent on TLR3 and UNC93B1 in all cells tested, but IFN-beta and/or -delta production in response to HSV-1 infection was impaired selectively in UNC93B-deficient neurons and oligodendrocytes. These cells were more susceptible to HSV-1 infection than control cells, whereas UNC93B1-deficient NSCs and astrocytes were not. Wolf et al. (2024) identified 4 patients with SLE or chillblain lupus and either homozygous (E92G) or heterozygous (R336L) for variants that led to selective TLR7 hyperactivation with constitutive type I IFN signaling (PMID: 38207055). E92G led to protein instability with reduced TLR7 interaction, while R336L modified TLR7 ligand-binding properties by enhancing TIR domain dimerization and promoting signaling initiation. Mishra et al. (2024) identified an UNC93B1 mutation in a patient with childhood-onset SLE that led to reduced BORC interaction and endosomal TLR7 accumulation, suggesting that failure to control TLR7 turnover is also sufficient to break immune tolerance to nucleic acids. At ESID 2024, Dr. M-L Fremond reported that in vitro and patient cell-based testing of these most recently identified variants showed differential gain of TLR7/8 activity. [Load More]