Secretory autophagy

Autophagy, once viewed exclusively as a cytoplasmic auto-digestive process, has its less intuitive but biologically distinct non-degradative roles. One manifestation of these functions of the autophagic machinery is the process termed secretory autophagy. Secretory autophagy facilitates unconventional secretion of the cytosolic cargo such as leaderless cytosolic proteins, which unlike proteins endowed with the leader (N-terminal signal) peptides cannot enter the conventional secretory pathway normally operating via the endoplasmic reticulum and the Golgi apparatus. Secretory autophagy may also export more complex cytoplasmic cargo and help excrete particulate substrates. Autophagic machinery and autophagy as a process also affect conventional secretory pathways, including the constitutive and regulated secretion, as well as promote alternative routes for trafficking of integral membrane proteins to the plasma membrane. Thus, autophagy and autophagic factors are intimately intertwined at many levels with secretion and polarized sorting in eukaryotic cells.

Introduction

The majority of eukaryotic secreted proteins are endowed with N-terminal signal peptides, which authorize them to enter the endoplasmic reticulum (ER) and follow a well-defined secretory pathway via the Golgi apparatus for delivery to the extracellular space (Figure 1). However, an exclusive subset of purely cytosolic proteins, lacking signal peptides and thus not capable of entering the ER, are nonetheless actively secreted from the cells to perform their extracellular biological functions. This phenomenon, termed unconventional secretion (Figure 1), includes several distinct processes [1, 2]. One form of unconventional secretion (secretory autophagy [3]) is associated specifically with the autophagy pathway defined by ATG factors that govern the biogenesis of autophagic membranes [4]. The ATG factors directing canonical autophagy include ULKs (mammalian paralogs of yeast Atg1, an upstream protein kinase), Beclins (mammalian paralogs of yeast Atg6, a key component of the lipid kinase VPS34, which generates phosphatidylinositiol 3-phosphate/PI3P), and LC3s and GABARAPs (mammalian paralogs of the yeast Atg8). Classically, the above factors result in the formation of double membrane autophagosomes, which in cooperation with cargo receptors such as p62/SQSTM1 [5], capture and eliminate cytoplasmic components. Conventionally, this occurs through degradation upon fusion of autophagosomes with lysosomes. In contrast to degradative autophagy, the autophagic machinery, through a shared but partially divergent pathway, may lead to secretion/expulsion of cytoplasmic constituents instead of their degradation. Either way, the cell gets rid of the captured cytoplasmic material, but the biological functions and repercussions are different.

The degradative canonical autophagy pathway, also referred to as macroautophagy, is classically considered together with microautophagy and chaperone-mediated autophagy as a collection of cytoplasmic self-digestion processes merging with lysosomes, whereby they carry out: (i) nutrient recycling functions at times of starvation by bulk digestion of the cytoplasm [6]; and (ii) cytoplasmic quality control functions [7] by removing a wide spectrum of substrates such as aggregation-prone or aggregated proteins [5, 8], damaged organelles such as irreversibly depolarized mitochondria [9], and invading microbes [10]. These well-studied aspects of degradative autophagy render it an attractive target for disease treatments [11]. In contrast to degradative autophagy, it has become slowly but increasingly apparent that autophagy has other, sometimes biogenesis-associated functions as well as a role in unconventional secretion (secretory autophagy; Figure 2). Secretory autophagy exports a range of cytoplasmic substrates (Table 1) [2, 12, 13, 14, 15, 16••, 17•, 18••, 19, 20•, 21••]. This review primarily examines the developing concept of secretory autophagy including its cargo, biological functions, and the currently limited understanding of its regulation. We will furthermore provide a brief update on the complementary processes of autophagy intersections [15] with the conventional (constitutive and regulated) secretion as well as with vectorial membrane protein trafficking and polarized sorting in mammalian cells. Although these latter processes should not be confused with the sensu stricto secretory autophagy, they complete the picture of the multi-tiered overlaps between autophagy and secretion in eukaryotic cells.