MZB1 enables efficient interferon \u03b1 secretion in stimulated plasmacytoid dendritic cells

Tanya Kapoor,Edward J Pearce,Rudolf Grosschedl,Erika L Pearce,Mauro Corrado

doi:10.1038/s41598-020-78293-3

Tanya Kapoor, Edward J Pearce + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-78293-3

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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 μ 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) α 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 IFNα secretion by Mzb1−/− pDCs. Thus, MZB1 enables pDCs to secrete high amounts of IFNα by mitigating ER stress via the ATF6-mediated UPR.

Highlights

MZB1 is an endoplasmic reticulum (ER)-resident protein that plays an important role in the humoral immune response by enhancing the interaction of the μ immunoglobulin (Ig) heavy chain with the chaperone GRP94 and by augmenting the secretion of IgM
The level of MZB1 protein expression in plasmacytoid dendritic cells (pDCs) was similar to that found in marginal zone B cells (MzB) and higher than that detected in follicular B cells (FoB)
We and others have previously described the role of MZB1 as an ER resident co-chaperone of GRP94 that enhances the secretion of IgM and IgA and promotes plasma cell differentiation[25,26,28,45]

Summary

Introduction

MZB1 is an endoplasmic reticulum (ER)-resident protein that plays an important role in the humoral immune response by enhancing the interaction of the μ immunoglobulin (Ig) heavy chain with the chaperone GRP94 and by augmenting the secretion of IgM. Upon stimulation of the TLRs with an agonist, 60% of the pDCs transcriptome is dedicated to the expression and secretion of IFNα5, whereby each cell is capable of producing a staggering 1–3 picograms within 24 h5,6. Due to their high IFN production, pDCs play an important role in controlling the initial stage of viral infections. Statistical difference between the mean was analysed by an unpaired two-tailed Student’s t-test. (***) P ≤ 0.0005. ns, nonsignificant

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