MZB1 enables efficient interferon α secretion in stimulated plasmacytoid dendritic cells

Sci Rep. 2020 Dec 14;10(1):21626. doi: 10.1038/s41598-020-78293-3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Immunity, Humoral
  • Immunoglobulin mu-Chains / immunology
  • Immunoglobulin mu-Chains / metabolism
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism*
  • Mice
  • Molecular Chaperones / immunology
  • Molecular Chaperones / metabolism*
  • Primary Cell Culture
  • Signal Transduction

Substances

  • Immunoglobulin mu-Chains
  • Interferon-alpha
  • Molecular Chaperones
  • pERp1 protein, mouse