The clearance of dead cells by efferocytosis Boada-Romero, Emilio; Martinez, Jennifer; Heckmann, Bradlee L ...
Nature reviews. Molecular cell biology,
07/2020, Letnik:
21, Številka:
7
Journal Article
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Multiple modes of cell death have been identified, each with a unique function and each induced in a setting-dependent manner. As billions of cells die during mammalian embryogenesis and daily in ...adult organisms, clearing dead cells and associated cellular debris is important in physiology. In this Review, we present an overview of the phagocytosis of dead and dying cells, a process known as efferocytosis. Efferocytosis is performed by macrophages and to a lesser extent by other 'professional' phagocytes (such as monocytes and dendritic cells) and 'non-professional' phagocytes, such as epithelial cells. Recent discoveries have shed light on this process and how it functions to maintain tissue homeostasis, tissue repair and organismal health. Here, we outline the mechanisms of efferocytosis, from the recognition of dying cells through to phagocytic engulfment and homeostatic resolution, and highlight the pathophysiological consequences that can arise when this process is abrogated.
LC3-Associated Phagocytosis and Inflammation Heckmann, Bradlee L.; Boada-Romero, Emilio; Cunha, Larissa D. ...
Journal of Molecular Biology/Journal of molecular biology,
11/2017, Letnik:
429, Številka:
23
Journal Article
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LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B–light chain 3) is conjugated to phagosome membranes using a portion of the ...canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an “immunologically silent” clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.
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•Comprehensive overview of LC3-associated phagocytosis (LAP).•LAP bridges the phagocytic and autophagic pathways.•Signaling to LAP and regulation of LAP activation by the canonical autophagy machinery.•LAP quenches inflammation and shapes the immune response towards anti-inflammation.•LAP promotes the immunosilent clearance of dying cells and prevents autoimmunity.
Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding ...complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here, we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single-cell RNA sequencing (RNA-seq) analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti-tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP.
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•LAP occurs as dead cells are engulfed in the tumor microenvironment•TAM lacking LAP display M1 characteristics and compromise tumors•TAM lacking LAP engage STING-dependent type I IFN production•TAM lacking LAP promote anti-tumor T cell responses
Impairment of LC3-associated phagocytosis in myeloid cells of the tumor microenvironment has anti-tumor effects.
Selective autophagy underlies many of the important physiological roles that autophagy plays in multicellular organisms, but the mechanisms involved in cargo selection are poorly understood. Here we ...describe a molecular mechanism that can target conventional endosomes for autophagic degradation. We show that the human transmembrane protein TMEM59 contains a minimal 19‐amino‐acid peptide in its intracellular domain that promotes LC3 labelling and lysosomal targeting of its own endosomal compartment. Interestingly, this peptide defines a novel protein motif that mediates interaction with the WD‐repeat domain of ATG16L1, thus providing a mechanistic basis for the activity. The motif is represented with the same ATG16L1‐binding ability in other molecules, suggesting a more general relevance. We propose that this motif may play an important role in targeting specific membranous compartments for autophagic degradation, and therefore it may facilitate the search for adaptor proteins that promote selective autophagy by engaging ATG16L1. Endogenous TMEM59 interacts with ATG16L1 and mediates autophagy in response to Staphylococcus aureus infection.
A new ATG16L1‐binding motif identified in several innate immune response proteins is involved in a non‐classical form of autophagy in response to bacterial infection.
A coding polymorphism of human ATG16L1 (rs2241880; T300A) increases the risk of Crohn's disease and it has been shown to enhance susceptibility of ATG16L1 to caspase cleavage. Here we show that T300A ...also alters the ability of the C-terminal WD40-repeat domain of ATG16L1 to interact with an amino acid motif that recognizes this region. Such alteration impairs the unconventional autophagic activity of TMEM59, a transmembrane protein that contains the WD40 domain-binding motif, and disrupts its normal intracellular trafficking and its ability to engage ATG16L1 in response to bacterial infection. TMEM59-induced autophagy is blunted in cells expressing the fragments generated by caspase processing of the ATG16L1-T300A risk allele, whereas canonical autophagy remains unaffected. These results suggest that the T300A polymorphism alters the function of motif-containing molecules that engage ATG16L1 through the WD40 domain, either by influencing this interaction under non-stressful conditions or by inhibiting their downstream autophagic signalling after caspase-mediated cleavage.
Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still ...unclear. Here we show that the anti-inflammatory protein A20 and the critical autophagic mediator Atg16l1 physically interact and synergize to regulate the stability of the intestinal epithelial barrier. A proteomic screen using the WD40 domain of ATG16L1 (WDD) identified A20 as a WDD-interacting protein. Loss of A20 and Atg16l1 in mouse intestinal epithelium induces spontaneous IBD-like pathology, as characterized by severe inflammation and increased intestinal epithelial cell death in both small and large intestine. Mechanistically, absence of A20 promotes Atg16l1 accumulation, while elimination of Atg16l1 or expression of WDD-deficient Atg16l1 stabilizes A20. Collectively our data show that A20 and Atg16l1 cooperatively control intestinal homeostasis by acting at the intersection of inflammatory, autophagy and cell death pathways.
ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show ...that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators.
The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer’s Disease. We have identified a novel non-canonical ...function of several autophagy proteins in the conjugation of LC3 to Rab5+, clathrin+ endosomes containing β-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from β-amyloid deposition.
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•LC3-associated endocytosis (LANDO) requires Rubicon and ATG5, but not FIP200•LANDO is required for recycling of Aβ receptors including TREM2 in microglia.•LANDO confers protection against Aβ deposition and murine Alzheimer’s disease (AD)•Microglial LANDO protects against neuronal loss and memory impairment in murine AD
An LC3-associated endocytosis pathway involved in the recycling of amyloid receptors is essential for the clearance of amyloid aggregates by microglia in a model of AD
In β-thalassemia, accumulated free α-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate β-thalassemia ...pathophysiology by degrading toxic free α-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51-like kinase 1 (
) gene in β-thalassemic mice reduces autophagic clearance of α-globin in red blood cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy-related 5 (
) gene has relatively minor effects. Systemic treatment with the mTORC1 inhibitor rapamycin reduces α-globin precipitates and lessens pathologies in β-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from CD34
cells of β-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating β-thalassemia.
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