Alloatti, A. | bioRxiv Science

bioRxiv2022

Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

immunology↗

bioRxiv2020

Small molecule enhancers of endosome-to-cytosol import augment anti-tumour immunity

Efficient cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumour immune responses. Yet, several steps of antigen intracellular traffic during cross-presentation are incompletely understood: in particular, the molecular mechanisms and the relative importance of antigen import from endocytic compartments into the cytosol. Here, we asked whether antigen import into the cytosol is rate-limiting for cross-presentation and anti-tumour immunity. By screening 700 FDA-approved drugs, we identified 37 import enhancers. We focused on prazosin and tamoxifen, and generated proteomic organellar maps of drug-treated DCs, covering the subcellular localisations of over 2000 proteins. By combining organellar mapping, quantitative proteomics, microscopy, and bioinformatics, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release into the cytosol. Enhancing antigen import facilitates cross-presentation of both soluble and cell-associated antigens. Systemic administration of prazosin also led to reduced growth of MC38 tumours and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumour immune responses and efficacy of checkpoint blockers. HighlightsO_LIQuinazolamine derivatives are potent enhancers of antigen import into the cytosol C_LIO_LIAntigen import enhancement occurs as a consequence of lysosomal trapping C_LIO_LIAntigen import enhancers facilitate cross-presentation and synergise with PD-L1 C_LIO_LIProteomic organellar maps of cDC1s as a tool to detect biological effects of drugs C_LI O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/079491v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1d55245org.highwire.dtl.DTLVardef@c3d43org.highwire.dtl.DTLVardef@189fbc8org.highwire.dtl.DTLVardef@1f1280e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗