UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice

Abstract

Recent advances in genetic analyses have significantly refined human type 1 diabetes (T1D) associated loci. The goal of such effort is to identify the causal genes and have a complete understanding of the molecular pathways that independently or interactively influence cellular processes leading to the destruction of insulin producing pancreatic β cells. UBASH3A has been suggested as the underlying gene for a human T1D associated region on chromosome 21. To further evaluate the role of UBASH3A in T1D, we targeted Ubash3a in NOD mice using zinc-finger nuclease mediated mutagenesis. In both 10-week-old females and males, significantly more advanced insulitis was observed in UBASH3A-deficient than in wild-type NOD mice. Consistently, UBASH3A-deficient NOD mice developed accelerated T1D in both sexes, which was associated with increased accumulation of β-cell autoreactive T cells in the spleen and pancreatic lymph node. Adoptive transfer of splenic T cells into NOD.Rag1-/mice demonstrated that UBASH3A deficiency in T cells was sufficient to promote T1D development. Our results provide strong evidence to further support a role of UBASH3A in T1D. In addition to T1D, UBASH3A deficiency also promoted salivary gland inflammation in females, demonstrating its broad impact on autoimmunity. Genetic susceptibility and its interaction with incompletely defined environmental factors promote the development of type 1 diabetes (T1D) 1. Human genome wide association studies (GWAS) have identified more than 50 genetic loci significantly linked to T1D 2,3. While the greatest genetic contribution is provided by certain human leukocyte antigen (HLA) haplotypes, non-HLA susceptibility genes also convey significant risk for T1D development. However, our knowledge of the underlying genes within these mapped GWAS regions is incomplete. One such region is on chromosome 21, of which UBASH3A has been indicated as the underlying gene. Recent fine mapping studies identified several T1D-associated non-coding single nucleotide polymorphisms (SNPs) in UBASH3A 3. Subsequent studies further linked UBASH3A risk alleles to its elevated expression and reduced interleukin (IL)-2 production in human CD4 T cells, providing additional evidence to support it as a causal gene in this T1D region 4,5. UBASH3A belongs to the ubiquitin-associated and Src-homology 3 domain containing (UBASH3) family that also includes a second member UBASH3B 6. Expression of UBASH3A is restricted to lymphoid tissues and primarily in T cells 7. On the other hand, UBASH3B is ubiquitously expressed 8. An earlier study indicated that T cells deficient in both UBASH3A and UBASH3B were hyperreactive to T cell receptor (TCR) stimulation and the double knockout mice were more susceptible to experimental autoimmune encephalomyelitis compared to the wild-type control 7. More recently, it was demonstrated that deficiency in either UBASH3A or UBASH3B alone had distinct effects in promoting trinitrobenzene sulfonic acid induced colitis in mice 9. UBASH3B suppresses TCR signaling by dephospho...

De‐coding genetic risk variants in type 1 diabetes

“…40,41 Moreover, the Diabetes Autoimmunity Study in the Young (DAISY) observed that non-coding UBASH3A risk variants were associated with progression from islet autoimmunity to overt disease, and children possessing these variants were more likely to develop T1D by the age of 15. 42 Despite decreased UBASH3A expression being associated with T1D protection in humans, murine studies have shown complete Ubash3a deficiency to accelerate T1D 43 and to protect from systemic Candida albicans infection, 44 suggesting that UBASH3A levels require fine-tuning to simultaneously prevent infections and to avoid autoimmunity.…”

Integrated bioinformatics analysis reveals novel key biomarkers in diabetic nephropathy

“…Accumulating evidence showed that altered expression of genes such as MDK (midkine) 80 , CCR2 81 , SAA1 82 , C3 83 , CD19 84 , CCR5 85 , CXCR3 86 , FABP4 87 , GDF15 88 , IGF2 89 , IGFBP1 90 and IL6 91 are important in the progression of DN. A previous study has shown that UBASH3A 92 , SIRPG (signal regulatory protein gamma) 93 , IKZF3 94 , CD1D 95 , CD2 96 , CD48 97 , CD247 98 and CYP27B1 99 are liable for progression of type 1 diabetes mellitus. The studies have shown that expression of SIT1 100 , JAML (junction adhesion molecule like) 101 , TIMP1 102 , PRKCB (protein kinase C beta) 103 , MMP7 104 , WNT7B 105 , WNT10A 106 , DUSP1 107 , WT1 108 , APOC3 109 , ERRFI1 110 , HCN2 111 , MME (membrane metalloendopeptidase) 112 , STRA6 113 , SLC12A3 114 and GC (GC vitamin D binding protein) 115 expedites epithelial to mesenchymal transition and renal brosis in DN.…”

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in diabetic nephropathy

“…MDK (midkine) [73], CCR2 [74], SAA1 [75], C3 [76], CD19 [77], CCR5 [78], CXCR3 [79], FABP4 [80], GDF15 [81], IGF2 [82], IGFBP1 [83] and IL6 [84] are important in the progression of DN through in ammation. A previous study has shown that UBASH3A [85], SIRPG (signal regulatory protein gamma) [86], IKZF3 [87], CD1D [88], CD2 [89], CD48 [90], CD247 [91] and CYP27B1 [92] are liable for progression of type 1 diabetes through in ammation, but these genes might be key for progression of DN. SIT1 [93], JAML (junction adhesion molecule like) [94], TIMP1 [95], PRKCB (protein kinase C beta) [96], MMP7 [97], WNT7B [98], WNT10A [99], DUSP1 [100], WT1 [101], APOC3 [102], ERRFI1 [103], HCN2 [104], MME (membrane metalloendopeptidase) [105], STRA6 [106], SLC12A3 [107] and GC (GC vitamin D binding protein) [108] expedites epithelial to mesenchymal transition and renal brosis in DN.…”