Oxidized lipids keep heat shock chaperones busy: new insights on the deficiencies of tumour-associated dendritic cells

Abstract In a recent publication in Nature Communications the group of Dr. Dmitry Gabrilovich takes us one step closer to understanding why lipid accumulation impairs the function of tumour-associated dendritic cells (DCs). In this study, the authors present two surprising and significant findings. First, they show that in mouse DCs oxidized lipids function as a sink that traps the heat shock chaperone HSP70, a molecular target of emerging anti-cancer strategies. Secondly, they find that HSP70 in turn regulates the trafficking of peptide-loaded major histocompatibility complex class I (pMHC-I) molecules, a complex that triggers the proliferation of cancer-killing T cells. These observations are discussed briefly in the context of lipid droplet function and pMHC-I trafficking in tumour-associated DCs, as well as HSP70’s pleiotropic and incompletely understood roles - and what they mean for future cancer therapy designs

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites - 3 of 5

AbstractPrimary data linked to the publication "Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites" in Communications Biology Criado-Santos et al 2023. Archive 1 of 5 including Figure

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites - 2 of 5

AbstractPrimary data linked to the publication "Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites" in Communications Biology Criado-Santos et al 2023. Archive 1 of 5 including Figures 4a-

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites - 5 of 5

AbstractPrimary data linked to the publication "Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites" in Communications Biology Criado-Santos et al 2023. Archive 5 of 5 including Figure 7 and Supplementary Figures S1 to S

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites - 1 of 5

AbstractPrimary data linked to the publication "Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites" in Communications Biology Criado-Santos et al 2023. Archive 1 of 5 including Figures 1 to 3 and 4c-

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites - 4 of 5

AbstractPrimary data linked to the publication "Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites" in Communications Biology Criado-Santos et al 2023. Archive 4 of 5 including Figure

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites

Primary data linked to the publication "Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites" in Communications Biology Criado-Santos et al 2023. The dataset is subdivided into a collection of 5 archives

The role of STIM and ORAI proteins in phagocytic immune cells

Phagocytic cells, such as neutrophils, macrophages, and dendritic cells, migrate to sites of infection or damage and are integral to innate immunity through two main mechanisms. The first is to directly neutralize foreign agents and damaged or infected cells by secreting toxic substances or ingesting them through phagocytosis. The second is to alert the adaptive immune system through the secretion of cytokines and the presentation of the ingested materials as antigens, inducing T cell maturation into helper, cytotoxic, or regulatory phenotypes. While calcium signaling has been implicated in numerous phagocyte functions, including differentiation, maturation, migration, secretion, and phagocytosis, the molecular components that mediate these Ca(2+) signals have been elusive. The discovery of the STIM and ORAI proteins has allowed researchers to begin clarifying the mechanisms and physiological impact of store-operated Ca(2+) entry, the major pathway for generating calcium signals in innate immune cells. Here, we review evidence from cell lines and mouse models linking STIM and ORAI proteins to the control of specific innate immune functions of neutrophils, macrophages, and dendritic cells

The ER phagosome connection in the era of membrane contact sites

Phagocytosis is an essential mechanism through which innate immune cells ingest foreign material that is either destroyed or used to generate and present antigens and initiate adaptive immune responses. While a role for the ER during phagosome biogenesis has been recognized, whether fusion with ER cisternae or vesicular derivatives occurs has been the source of much contention. Membrane contact sites (MCS) are tight appositions between ER membranes and various organelles that coordinate multiple functions including localized signalling, lipid transfer and trafficking. The discovery that MCS form between the ER and phagosomes now begs the question of whether MCS play a role in connecting the ER to phagosomes under different contexts. In this review, we consider the implications of MCS between the ER and phagosomes during cross-presentation and infection with intracellular pathogens. We also discuss the similarities between these contacts and those between the ER and plasma membrane and acidic organelles such as endosomes and lysosomes. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann

The role of calcium signaling in phagocytosis

Immune cells kill microbes by engulfing them in a membrane-enclosed compartment, the phagosome. Phagocytosis is initiated when foreign particles bind to receptors on the membrane of phagocytes. The best-studied phagocytic receptors, those for Igs (FcgammaR) and for complement proteins (CR), activate PLC and PLD, resulting in the intracellular production of the Ca(2+)-mobilizing second messengers InsP3 and S1P, respectively. The ensuing release of Ca(2+) from the ER activates SOCE channels in the plasma and/or phagosomal membrane, leading to sustained or oscillatory elevations in cytosolic Ca(2+) concentration. Cytosolic Ca(2+) elevations are required for efficient ingestion of foreign particles by some, but not all, phagocytic receptors and stringently control the subsequent steps involved in the maturation of phagosomes. Ca(2+) is required for the solubilization of the actin meshwork that surrounds nascent phagosomes, for the fusion of phagosomes with granules containing lytic enzymes, and for the assembly and activation of the superoxide-generating NADPH oxidase complex. Furthermore, Ca(2+) entry only occurs at physiological voltages and therefore, requires the activity of proton channels that counteract the depolarizing action of the phagocytic oxidase. The molecules that mediate Ca(2+) ion flux across the phagosomal membrane are still unknown but likely include the ubiquitous SOCE channels and possibly other types of Ca(2+) channels such as LGCC and VGCC. Understanding the molecular basis of the Ca(2+) signals that control phagocytosis might provide new, therapeutic tools against pathogens that subvert phagocytic killing