Significance It is known that autophagy plays a major role in cellular homeostasis and impaired autophagy has been implicated in various forms of human disease. Here we investigate one way in which ...autophagy is critically connected to cellular integrity by showing that autophagy loss diminishes DNA repair by the error-free process, homologous recombination. As a result, this causes reliance on the error-prone process of nonhomologous end joining for repair of DNA double-strand breaks, providing one explanation of why autophagy-deficient cells accumulate genomic damage. These findings therefore have important implications for diseases in which autophagy is impaired and for therapeutic strategies designed to inhibit autophagy, particularly if autophagy inhibition is undertaken in combination with agents that cause genomic damage.
(Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the error-free DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.
Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We ...report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation.
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•DRAM-1 is required for efficient activation of the nutrient-sensing complex mTORC1•DRAM-1 and SCAMP3 direct newly synthesized amino acid transporters to lysosomes•DRAM-1 drives lysosomal amino acid efflux to promote mTORC1 activation•Loss of DRAM-1 increases insulin sensitivity and enhances adipocyte differentiation
mTORC1 is a nutrient-sensing complex that affects many cellular processes. Beaumatin et al. show that DRAM-1 and SCAMP3 are required for efficient activation of mTORC1. Consequently, they show that loss of DRAM-1 impairs cell growth and amino-acid-induced autophagy repression while promoting insulin sensitivity, glycemic regulation, and adipocyte differentiation.
Core Ideas
OZCAR is a network of sites studying the critical zone.
OZCAR covers various disciplines.
OZCAR will help disciplines to work together for a better representation and modeling of the ...critical zone.
The French critical zone initiative, called OZCAR (Observatoires de la Zone Critique–Application et Recherche or Critical Zone Observatories–Application and Research) is a National Research Infrastructure (RI). OZCAR‐RI is a network of instrumented sites, bringing together 21 pre‐existing research observatories monitoring different compartments of the zone situated between “the rock and the sky,” the Earth's skin or critical zone (CZ), over the long term. These observatories are regionally based and have specific initial scientific questions, monitoring strategies, databases, and modeling activities. The diversity of OZCAR‐RI observatories and sites is well representative of the heterogeneity of the CZ and of the scientific communities studying it. Despite this diversity, all OZCAR‐RI sites share a main overarching mandate, which is to monitor, understand, and predict (“earthcast”) the fluxes of water and matter of the Earth's near surface and how they will change in response to the “new climatic regime.” The vision for OZCAR strategic development aims at designing an open infrastructure, building a national CZ community able to share a systemic representation of the CZ, and educating a new generation of scientists more apt to tackle the wicked problem of the Anthropocene. OZCAR articulates around: (i) a set of common scientific questions and cross‐cutting scientific activities using the wealth of OZCAR‐RI observatories, (ii) an ambitious instrumental development program, and (iii) a better interaction between data and models to integrate the different time and spatial scales. Internationally, OZCAR‐RI aims at strengthening the CZ community by providing a model of organization for pre‐existing observatories and by offering CZ instrumented sites. OZCAR is one of two French mirrors of the European Strategy Forum on Research Infrastructure (eLTER‐ESFRI) project.
SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of ...deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.
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