Expression of signal-transducing adaptor protein-1 attenuates experimental autoimmune hepatitis via down-regulating activation and homeostasis of invariant natural killer T cells

Abstract

Objective Signal-transducing adaptor protein (STAP) family members function as adaptor molecules and are involved in several events during immune responses. Notably however, the biological functions of STAP-1 in other cells are not known. We aimed to investigate the functions of STAP-1 in invariant natural killer T (iNKT) cells and iNKT cell-dependent hepatitis. Methods We employed concanavalin A (Con A)-induced hepatitis and α-galactosylceramide (α-GalCer)-induced hepatitis mouse models, both are models of iNKT cell-dependent autoimmune hepatitis, and STAP-1 overexpressing 2E10 cells to investigate the role of STAP-1 in iNKT cell activation in vivo an in vitro, respectively. Results After Con A- or α-GalCer-injection, hepatocyte necrotic areas and plasma alanine aminotransferase elevation were more severe in STAP-1 knockout (S1KO) mice and milder in lymphocyte-specific STAP-1 transgenic (S1Tg) mice, as compared to wild-type (WT) mice. Two events that may be related to Con A-induced and/or α-GalCer-induced hepatitis were influenced by STAP-1 manipulation. One is that iNKT cell populations in the livers and spleens were increased in S1KO mice and were decreased in S1Tg mice. The other is that Con A-induced interleukin-4 and interferon-γ production was attenuated by STAP-1 overexpression. These effects of STAP-1 were confirmed using 2E10 cells overexpressing STAP-1 that showed impairment of interleukin-4 and interferon-γ production as well as phosphorylation of Akt and mitogen-activated protein kinases in response to Con A stimulation. Conclusions These results conclude that STAP-1 regulates iNKT cell maintenance/activation, and is involved in the pathogenesis of autoimmune hepatitis.

Positive interactions between STAP-1 and BCR-ABL influence chronic myeloid leukemia cell proliferation and survival

“…STAP-1 mutations have been identified in DNA samples from patients with autosomal dominant hypercholesterolemia [21,22], although the effects of STAP-1 in cholesterol homeostasis remain controversial [23,24]. STAP-1 is also involved in autoimmune hepatitis pathogenesis through the regulation of iNKT cell maintenance and/or activation [13]. Microarray data from 572 patients with CML have showed that STAP-1 expression is increased in about 20% samples including ALL with or without BCR-ABL fusion gene [25].…”

“…Expression vectors for BCR-ABL and STAT5a and their mutant constructs were described previously [8,10]. Myc-tagged STAP-1 was described previously [13]. FLAG-tagged PU.1, RUNX3, NFATc1, and Myc-tagged-STAP-1 deletion mutants were generated by PCR methods and sequenced (primer sequences are available upon request).…”

Identification of differentially expressed genes and enriched pathways in inflammatory bowel disease using bioinformatics and next generation sequencing data analysis

“…Studies have reported that IL2 [371], IGFBP3 [372], IFNG (interferon gamma) [373], GDF15 [374], ACE2 [375] and IGFBP2 [376] could be related to malnutrition. IL2 [377], IGFBP3 [378], FASLG (Fas ligand) [379], BTNL2 [380], ADAMTS1 [381], S100B [382], STAP1 [383], CD160 [384], BANK1 [385], COL4A3 [386], IFNG (interferon gamma) [387], COCH (cochlin) [388], AKT3 [389], CCR4 [390], RAG1 [391], SEMA3A [392], CD200 [393], MYBL1 [394], FCRL3 [395], CD83 [396], GPR174 [397], CD19 [398], IL5 [399], EPHA4 [400], XCL1 [401], IL7R [402], CD180 [403], PRF1 [404], CXCR5 [405], ITM2A [406], ANXA1 [407], CCR6 [408], SLC4A4 [409], GZMB (granzyme B) [410], CD69 [411], BTLA (B and T lymphocyte associated) [412], IGF2 [413], SDC1 [414], MMP9 [415], GDF15 [416], C1QA [417], HRH3 [418], ACE2 [419...…”

Signal-transducing adaptor protein-2 modulates T-cell functions

“…STAP-1 gene mutations have been shown in some patients with autosomal dominant hypercholesterolemia [24,25]; however, the STAP-1's functional role in cholesterol homeostasis remains questionable [26,27]. STAP-1 acts to control the maintenance and activation of invariant natural killer (NK) T-cells and is involved in the pathogenesis of autoimmune hepatitis [28]. STAP-1 also plays a critical role in the maintenance of chronic myeloid leukemia leukemic stem cells [29].…”