Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation

doi:10.1016/j.tcb.2012.04.008

Trends in Cell Biology

Volume 22, Issue 8, August 2012, Pages 397-406

https://doi.org/10.1016/j.tcb.2012.04.008 Get rights and content

Autophagy is a cell biological process ubiquitous to all eukaryotic cells, often referred to as a catabolic, lysosomal degradative pathway. However, current studies in mammalian systems suggest that autophagy plays an unexpectedly broad biogenesis role in protein trafficking and secretion. Autophagy supports alternative trafficking pathways for delivery of integral membrane proteins to the plasma membrane and affects secretion, including the constitutive, regulated and unconventional secretion pathways. Autophagy-based unconventional secretion, termed here ‘autosecretion’, is one of the pathways enabling leaderless cytosolic proteins to exit the cell without entering the endoplasmic reticulum (ER)-to-Golgi secretory pathway. In this review, we discuss the emerging underlying mechanisms of how autophagy affects different facets of secretion. We also describe the physiological roles of autosecretory cargos that are often associated with inflammatory processes and also play a role in the formation of specialized tissues and in tissue remodeling, expanding the immediate sphere of influence of autophagy from the intracellular to the extracellular space.

Section snippets

Role of autophagy in biology exceeds degradation and catabolism

Sensu stricto autophagy (often referred to as macroautophagy) is a ubiquitous eukaryotic process dependent on evolutionarily conserved Atg (autophagy) factors and on the formation of specialized internal membrane domains in the cytoplasm that form unique organelles called autophagosomes [1]. Autophagosomes capture various cytoplasmic cargo with different end purposes that typically fall into one of the following general categories: (i) quality control and removal of potentially harmful

Autophagy as a cell biological pathway

For a comprehensive review of autophagy factors in yeast, their equivalents in higher eukaryote cells and additional factors controlling autophagy in mammalian cells, see [1]. In this section we cover aspects of autophagosome membrane biology that may be useful in understanding the connections of the autophagic machinery with the secretory manifestations discussed in this review. Autophagosomes are believed to emerge at least in part from ER membranes 22, 23 via an ER cradle model, with the

Autophagy-based unconventional secretion (autosecretion)

The role of autophagy in protein secretion and trafficking is a relatively recently recognized function of the autophagic machinery (Figure 2, pathways 1–3). One breakthrough in this area was the realization that a subset of unconventionally secreted cytosolic proteins, which lack leader peptides and thus cannot enter the conventional ER-to-Golgi secretory pathway, depend on autophagy for extracellular export 18, 19, 20, 21 (Figure 2, pathway 3).

Unconventional secretion is a catch-all term for

Autophagy-based unconventional secretion, omegasome and CUPS

Information regarding how autophagy promotes unconventional secretion comes, at present, from a handful of studies 17, 18, 19, 20, 21. The omegasome, acting as a cradle for generating nascent autophagosomes [24], or a potentially related structure in yeast termed the compartment for unconventional protein secretion (CUPS) [19] (Figure 1, Figure 2) may represent the source of organelles or trafficking intermediates of the autosecretory pathway contributing to autophagy-based unconventional

Dual role of autophagy in unconventional secretion of alarmins and control of inflammasome activation

It may have appeared as a foregone conclusion that IL-1β, a leaderless cytosolic protein secreted from the cell via membranous organelles, would be a substrate for autophagy-based unconventional secretion, at least according to some predictions 18, 20, 56. However, this issue has been found to be far more complicated (Figure 3a–d). Numerous converging reports 21, 57, 58, 59, 60 of studies on the effects of autophagy on IL-1β from the immunological perspective have unequivocally indicated that

Autophagy and GRASP in unconventional trafficking of proteins to plasma membrane

The role of GRASP and autophagy in vectorial transport of proteins is not limited to autosecretion of leaderless cytosolic proteins but also involves unconventional trafficking of integral membrane proteins to polarized domains of the plasma membrane, bypassing the conventional ER–Golgi–plasma membrane pathway. Recently, ΔF508 CFTR, the most common form of mutant CFTR protein causing cystic fibrosis, was shown to utilize ATG5- and ATG7-dependent, as well as GRASP55-dependent, unconventional

Autophagy and constitutive secretion

A recent report [16] uncovered another intersection between autophagy and the constitutive secretory pathway (Figure 2, pathway 2). In this case, the authors described the existence of a specialized compartment, TOR-autophagy spatial coupling compartment (TASCC), interfacing with autophagic degradation and indirectly favoring production of a subset of secreted proteins that utilize conventional (ER-to-Golgi-to-plasma membrane) secretion. TASCC is physically recognizable in senescent cells as a

Autophagy and regulated secretion

The effects of autophagy on secretion do not end with the constitutive conventional secretory pathway and unconventional secretion. Several studies have linked defects in autophagy or Atg genes to alterations in regulated secretion (Figure 2, pathway 1) delivering the contents stored in secretory granules or lysosomes 10, 11, 12. A forerunner of the role of autophagy in the above events is the report of enhanced Atg-dependent fusion between phagosomes and lysosomes in the process of microbial

Concluding remarks

The newly uncovered numerous intersections of autophagy with biosynthetic processes such as conventional and unconventional secretion of biologically active cargo and trafficking of integral membrane proteins expand the range of physiological roles of autophagy. Several specialized tissues and organs are influenced by autophagic machinery in this biogenesis role. Bone remodeling by osteoclasts [11], melanosome maturation in skin melanocytes and retinal pigment epithelial cells [15], and

Acknowledgments

The author thanks Dara Elerath for graphic design, and funding agencies for grant support (AI042999, AI069345, and ARRA RC1AI086845 from National Institutes of Health, Crohn's and Colitis Foundation of America CCFA2053, and Bill and Melinda Gates Grand Challenge Explorations grant).

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Trends in Cell Biology

ReviewAutophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation

Section snippets

Role of autophagy in biology exceeds degradation and catabolism

Autophagy as a cell biological pathway

Autophagy-based unconventional secretion (autosecretion)

Autophagy-based unconventional secretion, omegasome and CUPS

Dual role of autophagy in unconventional secretion of alarmins and control of inflammasome activation

Autophagy and GRASP in unconventional trafficking of proteins to plasma membrane

Autophagy and constitutive secretion

Autophagy and regulated secretion

Concluding remarks

Acknowledgments

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Mol. Cell

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Dev. Cell

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Mol. Cell

Curr. Opin. Cell Biol.

Cell

Dev. Cell

J. Biol. Chem.

Cell Metab.

Cell Metab.

Cell

Dev. Cell

Cell

The role of atg proteins in autophagosome formation

Annu. Rev. Cell Dev. Biol.

Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

Nat. Cell Biol.

Mechanisms of mitophagy

Nat. Rev. Mol. Cell Biol.

Mitochondria and the autophagy-inflammation-cell death axis in organismal aging

Science

Autophagy and metabolism

Science

Autophagy in immunity and inflammation

Nature

A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells

Nature

Crucial role for autophagy in degranulation of mast cells

J. Allergy Clin. Immunol.

Autophagy is essential for mouse sense of balance

J. Clin. Invest.

Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice

Science

Genome-wide siRNA-based functional genomics of pigmentation identifies novel genes and pathways that impact melanogenesis in human cells

PLoS Genet.

Spatial coupling of mTOR and autophagy augments secretory phenotypes

Science

Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation

J. Cell Biol.

Review
Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation