MZB1 enables efficient interferon ? secretion in stimulated plasmacytoid dendritic cells.

ABSTRACT: MZB1 is an endoplasmic reticulum (ER)-resident protein that plays an important role in the humoral immune response by enhancing the interaction of the ? immunoglobulin (Ig) heavy chain with the chaperone GRP94 and by augmenting the secretion of IgM. Here, we show that MZB1 is also expressed in plasmacytoid dendritic cells (pDCs). Mzb1^-/- pDCs have a defect in the secretion of interferon (IFN) ? upon Toll-like receptor (TLR) 9 stimulation and a reduced ability to enhance B cell differentiation towards plasma cells. Mzb1^-/- pDCs do not properly expand the ER upon TLR9 stimulation, which may be accounted for by an impaired activation of ATF6, a regulator of the unfolded protein response (UPR). Pharmacological inhibition of ATF6 cleavage in stimulated wild type pDCs mimics the diminished IFN? secretion by Mzb1^-/- pDCs. Thus, MZB1 enables pDCs to secrete high amounts of IFN? by mitigating ER stress via the ATF6-mediated UPR.

SUBMITTER: Kapoor T 

PROVIDER: S-EPMC7736851 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature