Regulation of p38MAPK‐mediated dendritic cell functions by the deubiquitylase otubain 1

Abstract

Dendritic cells (DCs) are professional antigen presenting cells (APCs) that represent the essential link between innate and acquired immunity. Otubain (OTUB) 1 is shown to deubiquitinate TRAFs to suppress virus‐induced inflammatory response. MAPK, a downstream molecule of TRAFs, is involved in regulating LPS‐induced immune reactions and its activation is sensitive to the presence of OTUB1. Little is known about contributions of OTUB1 to changes in biological properties of DCs. The present study, therefore, explored whether DC functions are influenced by OTUB1. To this end, DCs were isolated and cultured with GM‐CSF to attain bone marrow‐derived DCs (BMDCs) and followed by treatment with lipopolysaccharide (LPS) in the presence or absence of OTUB1 siRNA. Expression of markers of cellular maturation and proliferation were analyzed by flow cytometry, and secretion of inflammatory cytokines and ability to stimulate CD4+ T‐cells in allogenic mixed leukocyte reaction (allo‐MLR) by ELISA, cell migration by a transwell migration assay and phagocytic capacity by FITC‐dextran uptake measurement. As a result, treatment of the cells with OTUB1 siRNA prolonged activation of p38MAPK, increased CD54 expression and IL‐6 release and reduced FITC‐dextran uptake. Moreover, cytokine release produced from CD4+ T‐cells in allo‐MLR was different. The enhanced level of IFN‐γ, but not other cytokine production was observed in the presence of siRNA OTUB1. All the effects were completely abolished when the cells were exposed with p38MAPK inhibitor SB203580. In conclusion, OTUB1 prevents the prolonged activation of p38MAPK, which in turn compromises DC functions.

Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles

“…Figure 4 b revealed several active candidates that regulated protein degradation, among which the OTU domain of ubiquitin aldehyde binding 1 (OTUB1) showed a significant decrease in ZnCM-treated igDCs compared with vehicle-treated igDCs. Previously, OTUB1 had emerged as an effective deubiquitinase to cleave K48-linked ubiquitin chains to inhibit protein degradation [ 59 ]. It was reported that OTUB1 deubiquitination is closely associated with the biological functions of DCs, which inhibit CD4 + T-cell proliferation and IFN-γ cytokine secretion in allogenic mixed lymphocyte reactions (allo-MLRs) [ 59 ].…”

“…Previously, OTUB1 had emerged as an effective deubiquitinase to cleave K48-linked ubiquitin chains to inhibit protein degradation [ 59 ]. It was reported that OTUB1 deubiquitination is closely associated with the biological functions of DCs, which inhibit CD4 + T-cell proliferation and IFN-γ cytokine secretion in allogenic mixed lymphocyte reactions (allo-MLRs) [ 59 ]. Our results suggested that ZnCM NPs significantly downregulated the expression of the deubiquitinase OTUB1 in igDCs.…”

Partial otubain 1 deficiency compromises fetal well-being in allogeneic pregnancies despite no major changes in the dendritic cell and T cell compartment

“…Moreover, we wondered whether a lack of OTUB1 on the maternal side would have any consequences for fetal well-being in a more physiological pregnancy setting, namely an allogeneic pregnancy. As OTUB1 was described to modulate DC and T cell functions [ 10 – 13 ] we hypothesized that its loss may provoke perturbances in maternal immune responses and thereby interfere with fetal tolerance induction. Indeed, we observed a significant increased number of resorbed fetuses in allogeneic pregnancies where dams showed a partial OTUB1 deficiency.…”

Molecular Mechanisms of DUBs Regulation in Signaling and Disease

“…Its subcellular location is regulated by casein kinase 2 (CK2), which phosphorylates Ser16 of OTUB1 moving it from the cytoplasm to the nucleus [141]. OTUB1 can participate in the regulation of p53 stability, immune response, signal transduction, DNA damage repair, and other biological processes [142][143][144][145][146]. OTUB1 is a K48 specific deubiquitinating enzyme, and in addition to the DUB activity, OTUB1 has also emerged as a special DUB that can suppress the activity of E2 conjugating enzymes, inhibiting thus the ubiquitination process [143].…”