The endoplasmic reticulum (ER) is a membranous intracellular organelle and the first compartment of the secretory pathway. As such, the ER contributes to the production and folding of approximately one-third of cellular proteins, and is thus inextricably linked to the maintenance of cellular homeostasis and the fine balance between health and disease. Specific ER stress signalling pathways, collectively known as the unfolded protein response (UPR), are required for maintaining ER homeostasis. The UPR is triggered when ER protein folding capacity is overwhelmed by cellular demand and the UPR initially aims to restore ER homeostasis and normal cellular functions. However, if this fails, then the UPR triggers cell death. In this review, we provide a UPR signalling-centric view of ER functions, from the ER's discovery to the latest advancements in the understanding of ER and UPR biology. Our review provides a synthesis of intracellular ER signalling revolving around proteostasis and the UPR, its impact on other organelles and cellular behaviour, its multifaceted and dynamic response to stress and its role in physiology, before finally exploring the potential exploitation of this knowledge to tackle unresolved biological questions and address unmet biomedical needs. Thus, we provide an integrated and global view of existing literature on ER signalling pathways and their use for therapeutic purposes.

The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics. Cellular organelles are no longer conceived as unconnected structures with isolated functions, but as dynamic and integrated compartments. The best-characterized membrane contact sites bridge the endoplasmic reticulum (ER) and mitochondria 1. The ER-the largest organelle in eukaryotic cells-controls protein folding, lipid synthesis and calcium storage. The folding capacity of the ER is constantly challenged by physiological demands and disease states. To sustain proteostasis, cells engage the unfolded protein response (UPR) 2 , a Carreras-Sureda et al.

The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca 2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER-mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER-mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER-mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth.Keywords: endoplasmic reticulum, mitochondria, mitochondria-associated membranes, Ca 2+ signaling, eR stress, autophagy, inflammasome, cancer cell Abbreviations: AA, arachidonoyl; ATF4, activating transcription factor 4; ATG, autophagy-related gene; Bcl-2, B-cell lymphoma 2; Bcl-XL, B-cell lymphoma-extra large; BECN1, Beclin-1; Ca 2 + , calcium; Cav-1, caveolin-1; CL, cardiolipin; CNX, calnexin; cyt c, cytochrome c; Drp1, dynamin-related protein 1; ER, endoplasmic reticulum; Grp78, glucose-regulated protein 78; HK2, hexokinase 2; IL-1β, interleukin 1β; IL-18, interleukin 18; IP3, inositol trisphosphate; IP3R, inositol 1, 4, 5-trisphosphate receptor; IP3R3, inositol 1, 4, 5-trisphosphate receptor 3; IRE1, inositol requiring enzyme 1; MAMs, mitochondria-associated membranes; MAVS, mitochondrial antiviral-signaling protein; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; mTORC2, mammalian target of rapamycin 2; NLRP3, NOD-like receptor family 3; OMM, outer mitochondrial membrane; ORP5, oxysterol-binding protein (OSBP)-related protein (ORP) 5; ORP8, oxysterol-binding protein (OSBP)-related protein (ORP) 8; PA, phosphatidic acid; PACS-2, phosphofurin acidic cluster sorting protein 2; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PERK, double stranded RNA-activated protein kinase (PKR)-like ER kinase; PI, phosphatidylinositol; PM, plasma membrane; PML, promyelocytic leukemia; PP2A, protein phosphatase 2A; PS, phosphatidylserine; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PTPIP51, protein tyrosine phosphatase-interacting protein 51; ROS, reactive oxygen species; SERCA, sarco/endoplasmic reticulum Ca 2+ ATPase; SERCA2b, sarco/endoplasmic reticulum Ca 2 + ATPase isoform 2b; Sigma1 receptor, S1R; StAR, cholesterol transport steroidogenic acute regula...

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Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5−/− mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.

Membrane contact sites (MCS) between organelles of eukaryotic cells provide structural integrity and promote organelle homeostasis by facilitating intracellular signaling, exchange of ions, metabolites and lipids and membrane dynamics. Cataloguing MCS revolutionized our understanding of the structural organization of a eukaryotic cell, but the functional role of MSCs and their role in complex diseases, such as cancer, are only gradually emerging. In particular, the endoplasmic reticulum (ER)-mitochondria contacts (EMCS) are key effectors of non-vesicular lipid trafficking, thereby regulating the lipid composition of cellular membranes and organelles, their physiological functions and lipid-mediated signaling pathways both in physiological and diseased conditions. In this short review, we discuss key aspects of the functional complexity of EMCS in mammalian cells, with particular emphasis on their role as central hubs for lipid transport between these organelles and how perturbations of these pathways may favor key traits of cancer cells.

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