Delivery of Cytosolic Components by Autophagic Adaptor Protein p62 Endows Autophagosomes with Unique Antimicrobial Properties

Ponpuak, Marisa; Davis, Alexander S.; Roberts, Esteban; Delgado, Mònica; Dinkins, Christina; Zhao, Zhen; Virgin, Herbert W.; Kyei, George B.; Johansen, Terje; Vergne, Isabelle; Deretic, Vojo

doi:10.1016/j.immuni.2010.02.009

Cited by 286 publications

(294 citation statements)

References 61 publications

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“…Induction of autophagy by IFN-g or rapamycin has also been shown to enhance mycobacterial killing (60). One of the mechanisms for this action involves delivery of cytosolic proteins by p62 to lysosomes where they become potent tuberculosis antibiotics (61).…”

Section: Alveolar Macrophagesmentioning

confidence: 99%

Regulation and Functional Significance of Autophagy in Respiratory Cell Biology and Disease

Patel

Morse

Choi

2013

Am J Respir Cell Mol Biol

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Autophagy is a homeostatic process common to all eukaryotic cells that serves to degrade intracellular components. Among three classes of autophagy, macroautophagy is best understood, and is the subject of this Review. The function of autophagy is multifaceted, and includes removal of long-lived proteins and damaged or unneeded organelles, recycling of intracellular components for nutrients, and defense against pathogens. This process has been extensively studied in yeast, and understanding of its functional significance in human disease is also increasing. This Review explores the basic machinery and regulation of autophagy in mammalian systems, methods employed to measure autophagic activity, and then focuses on recent discoveries about the functional significance of autophagy in respiratory diseases, including chronic obstructive pulmonary disease, cystic fibrosis, tuberculosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, acute lung injury, and lymphangioleiomyomatosis.Keywords: autophagy; chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; epithelial cells; fibroblasts Autophagy is an evolutionarily conserved process first described more than 50 years ago that is vital to cellular homeostasis. Many of the molecular events and pathways involved in autophagy were discovered in yeast cells, but knowledge of its function and regulation in mammalian systems has increased greatly in the last decade. Best studied in cancer and neurodegenerative diseases, its role in respiratory diseases is becoming increasingly important with each passing year. To date, it has been studied in chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, cystic fibrosis (CF), pulmonary arterial hypertension (PAH), tuberculosis, acute lung injury, and lymphangioleiomyomatosis. This Review first focuses on the basic mechanisms and regulation of autophagy, as well as the various techniques employed in its measurement in cells and tissues. We then turn to the functional significance of autophagy in the aforementioned respiratory diseases (Table 1). Given the cell-and environmentdependent nature of autophagy, the discussion of these diseases here are within the context of the major respiratory cell types. Continued elucidation of the functional role of autophagy in these lung diseases and others will allow better understanding of their pathophysiologic underpinnings and offer potential new diagnostic and/or therapeutic targets. CLASSES OF AUTOPHAGYThe term autophagy, derived from the Greek and meaning "self eating," comprises three related but distinct cellular processes that entail delivery of cytoplasmic components to lysosomes for degradation and recycling. Microautophagy involves nonselective envelopment of cytoplasmic components directly by lysosomes. Chaperone-mediated autophagy consists of selectively transporting cargo tagged by a pentapeptide motif to the lysosome, binding to lysosomal receptors, and translocation across the membrane. The third category of autophagy is macroautophagy. Th...

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Section: Alveolar Macrophagesmentioning

confidence: 99%

Regulation and Functional Significance of Autophagy in Respiratory Cell Biology and Disease

Patel

Morse

Choi

2013

Am J Respir Cell Mol Biol

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“…(46,45) adaptors, and receptors to deliver cargo into autophagosomes (8,9). Host ubiquitination of targets is a known autophagic signal that together with the adaptor protein p62 facilitates selective autophagy of many substrates including protein aggregates, peroxisomes, mitochondria (62), and bactericidal peptides (63). Ubiquitination also serves as a signal for recognition of cytosolic bacteria such as S. typhimurium (64).…”

Section: Yersinia Pseudotuberculosismentioning

confidence: 99%

“…Host autophagy uses the adaptor protein p62 to deliver ubiquitinated cytosolic proteins to autolysosomes, where they are converted into neo-bactericidal peptides that efficiently kill the entrapped M. tuberculosis (63,76). Furthermore, autophagy facilitates adaptive immune responses such as MHC class II antigen presentation (77), although this process might be more important in dendritic cells than in macrophages.…”

Section: Yersinia Pseudotuberculosismentioning

confidence: 99%

Autophagy as a macrophage response to bacterial infection

2012

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SummaryThe macrophage is a key component of host defense mechanisms against pathogens. In addition to the phagocytosis of bacteria and secretion of proinflammatory mediators by macrophages, autophagy, a process involved in turnover of cellular material, is a recently identified component of the immune response to bacterial infection. Despite the bactericidal effect of autophagy, some species of intracellular bacteria are able to survive by using one or more strategies to avoid host autophagic attack. Here, we review the latest findings on the interactions between bacteria and autophagy in macrophages.

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“…Atg8/LC3 catalyses hemifusion of membranes and might therefore support the elongation of the autophagosome membrane 17 . In addition, it is used to recruit autophagic cargo [18][19][20] . In addition to its role in autophagosome formation, Atg6/Beclin-1 containing PI3 kinase complexes are then once more involved in macroautophagy at the stage of autophagosome fusion with the lysosome [21][22][23][24] .…”

Section: T Cells Detect Infected or Transformed Cells Via Antigen Prementioning

confidence: 99%

MHC presentation via autophagy and how viruses escape from it

Gannagé

Münz

2010

Semin Immunopathol

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T cells detect infected and transformed cells via antigen presentation by major histocompatibility complex (MHC) molecules on the cell surface. For T cell stimulation, these MHC molecules present fragments of proteins that are expressed or taken up by the cell. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8(+) and on MHC class II molecules to helper CD4(+) T cells. Proteasomes are primarily involved in MHC class I ligand and lysosomes, in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape and could maybe be harnessed for immunotherapy. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8 + and on MHC class II molecules to helper CD4 + T cells.Proteasomes are primarily involved in MHC class I ligand, and lysosomes in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes, and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape, and could maybe be harnessed for immunotherapy. Gannage and Münz 3

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Delivery of Cytosolic Components by Autophagic Adaptor Protein p62 Endows Autophagosomes with Unique Antimicrobial Properties

Cited by 286 publications

References 61 publications

Regulation and Functional Significance of Autophagy in Respiratory Cell Biology and Disease

Regulation and Functional Significance of Autophagy in Respiratory Cell Biology and Disease

Autophagy as a macrophage response to bacterial infection

MHC presentation via autophagy and how viruses escape from it

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