Abstract
Autophagy was initially described as a catabolic pathway that recycles nutrients of cytoplasmic constituents after lysosomal degradation during starvation. Since the immune system monitors products of lysosomal degradation via major histocompatibility complex (MHC) class II restricted antigen presentation, autophagy was found to process intracellular antigens for display on MHC class II molecules. In recent years, however, it has become apparent that the molecular machinery of autophagy serves phagocytes in many more membrane trafficking pathways, thereby regulating immunity to infectious disease agents. In this minireview, we will summarize the recent evidence that autophagy proteins regulate phagocyte endocytosis and exocytosis for myeloid cell activation, pathogen replication, and MHC class I and II restricted antigen presentation. Selective stimulation and inhibition of the respective functional modules of the autophagy machinery might constitute valid therapeutic options in the discussed disease settings.
Highlights
Autophagy is a group of at least three pathways that deliver cytoplasmic constituents for lysosomal degradation [1]
The cascade of ULK1 and VPS34 complexes can put phosphoinositide marks on non-isolation membranes and the cascade of VPS34 and Atg8 lipidation complexes can label non-autophagosomal membranes with Atg8/LC3 [15, 16]. While these modules are successively used by macroautophagy to restrict intracellular pathogens, like bacteria and viruses [17,18,19], and to degrade intracellular proteins for major histocompatibility complex (MHC) class II restricted antigen presentation, during anti-viral immune responses and CD4+ T cell education [20, 21], individual modules are used in alternative pathways, including proviral roles in infectious viral particle release, restriction of phagocytosed bacteria, secretion of inflammatory mediators, and presentation of phagocytosed antigens on MHC molecules [22,23,24,25,26,27,28,29]
Aging of mice with macrophage deficiencies of Atg7, Atg5, Beclin-1, NADPH oxidase 2 (NOX2), or Rubicon developed signs of hyperinflammatory disease, while this phenotype was far less pronounced in mice with ULK1 and FIP200 deficiencies in macrophages [35]. These findings suggested that LC3-ASSOCIATED PHAGOCYTOSIS (LAP), but not classical macroautophagy, protects wild-type mice from this aging-related hyperinflammation
Summary
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland. Edited by: Geanncarlo Lugo-Villarino, UMR5089 Institut de Pharmacologie et de Biologie Structurale (IPBS), France. Since the immune system monitors products of lysosomal degradation via major histocompatibility complex (MHC) class II restricted antigen presentation, autophagy was found to process intracellular antigens for display on MHC class II molecules. It has become apparent that the molecular machinery of autophagy serves phagocytes in many more membrane trafficking pathways, thereby regulating immunity to infectious disease agents. In this minireview, we will summarize the recent evidence that autophagy proteins regulate phagocyte endocytosis and exocytosis for myeloid cell activation, pathogen replication, and MHC class I and II restricted antigen presentation.
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