SnapShot: Selective Autophagy

  • Jin M
  • Liu X
  • Klionsky D
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Abstract

There are various types of autophagy, which can be categorized as nonselective or selective. Macroautophagy is an evolutionarily conserved process through which cells degrade and recycle cytoplasm. Nonselective macroautophagy randomly engulfs a portion of the cytoplasm into autophagosomes and then delivers them to the vacuole (in fungi or plants) or the lysosome (in other higher eukaryotes) for degradation. Selective macroautophagy, however, specifically recognizes and degrades a particular cargo, either a protein complex, an organelle, or an invading microbe. The morphological hallmark of macroautophagy is the formation of an initial sequestering compartment, the phagophore, which expands into the double-membrane autophagosome; the initial sequestration occurs in a compartment that is separate from the degradative organelle. Selective microautophagy utilizes the same cellular machinery, but in this case, the sequestration event takes place directly at the limiting membrane of the lysosome/vacuole. In higher eukaryotes, selective types of autophagy also include chaperone-mediated autophagy (CMA), and two similar processes, endosomal microautophagy (e-MI) and chaperone-assisted selective autophagy (CASA), each of which involves uptake at the limiting membrane of either the lysosome or endosome. In all cases, how a substrate is targeted for sequestration and segregated from other parts of the cell is one of the major questions in this research field. Nonselective autophagy is primarily a starvation response, whereas cells use selective autophagy for a variety of purposes, including remodeling to adapt to changing environmental/nutritional conditions and to eliminate damaged organelles. Accordingly, defects in selective autophagy are associated with a range of pathophysiologies in humans, including certain types of neurodegenerative diseases. General Model Selective macroautophagy utilizes the same core machinery used for nonselective macroautophagy. A small number of additional proteins suffice to make the process selective; a cargo-ligand-receptor-scaffold model is proposed to describe how cells achieve selectivity (see table). The ligand is the recognition component on the cargo that binds a receptor. In some cases, the receptor is a resident protein on the cargo (e.g., Atg32 or BNIP3L/NIX, which are located in the mitochondria outer membrane, in mitophagy). The interaction between the receptor and scaffold is vital for cargo recruitment to the phapophore assembly site (PAS), where an autophagosome forms. In yeast, Atg11 is the most commonly used scaffold protein, mediating several types of selective macroautophagy, including the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy, pexophagy, and reticulophagy; however, in mammals a functional counterpart of Atg11 is yet to be discovered. In many cases, the receptor proteins subsequently bind Atg8, in yeast, or, in mammalian cells, one of the LC3 family proteins through a particular sequence referred to as AIM (Atg8-family-interacting motif) or LIR (LC3-interacting region). This interaction may connect the cargo directly with the macroautophagy machinery. Some aspects of this model can also be applied to CMA. In this case, the cargo is comprised of individual cytosolic proteins, which contain a consensus pentapeptide motif functioning as the ligand. The cytosolic chaperone HSPA8/HSC70 recognizes this sequence and delivers the substrate to LAMP2A in the NIH Public Access

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Jin, M., Liu, X., & Klionsky, D. J. (2013). SnapShot: Selective Autophagy. Cell, 152(1–2), 368-368.e2. https://doi.org/10.1016/j.cell.2013.01.004

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