The Cvt pathway as a model for selective autophagy

Abstract

Autophagy is a highly conserved, ubiquitous process that is responsible for the degradation of cytosolic components in response to starvation. Autophagy is generally considered to be non-selective; however, there are selective types of autophagy that use receptor and adaptor proteins to specifically isolate a cargo. One type of selective autophagy in yeast is the cytoplasm to vacuole targeting (Cvt) pathway. The Cvt pathway is responsible for the delivery of the hydrolase aminopeptidase I to the vacuole; as such, it is the only known biosynthetic pathway that utilizes the core machinery of autophagy. Nonetheless, it serves as a model for the study of selective autophagy in other organisms.

Figure 1. Three main types of autophagy

There are three main types of autophagy: chaperone-mediated autophagy, microautophagy, and macroautophagy. The schematic depicts a mixture of these processes in lower and higher eukaryotes. For example, the lysosome is much smaller than the fungal vacuole. Also, chaperone-mediated autophagy has only been characterized in higher eukaryotes, whereas microautophagy and macroautophagy are evolutionarily conserved. Macroautophagy is the best-characterized pathway out of the three and the hallmark of this process is the formation of a double-membrane vesicle that non-selectively sequesters cytoplasmic components and delivers them to the lysosome or vacuole for degradation and recycling of the cargo.

Figure 2. Classification of Atg proteins according to function

Autophagy-related (Atg) proteins can be classified according to their role in selective and nonselective autophagy. There are 17 Atg proteins that are required for both types, and these are named the core machinery. Selective autophagy is represented by the cytoplasm to vacuole targeting (Cvt) pathway, mitophagy and pexophagy.

Figure 3. Cvt vesicle formation

Precursor Ape1 is a proenzyme that is synthesized in the cytosol, and rapidly oligomerizes to form a homododecamer. The dodecamer further organizes into a higher order structure termed the Ape1 complex. The receptor protein, Atg19, then binds to the Ape1 complex forming the Cvt complex. The Ams1 oligomer is also able to bind Atg19 and can be incorporated into the same Cvt complex. Atg11 binds to Atg9 and transports the Cvt complex to the PAS. At the PAS the Cvt complex binds to the expanding phagophore membrane through an interaction between Atg19 and Atg8–PE. Transport of the Cvt complex to the PAS and the expansion of the phagophore require the actin cytoskeleton and the VFT complex, respectively; delivery of membrane to the expanding vesicle likely involves cycling of Atg9. The phagophore membrane expands around the Cvt complex (excluding bulk cytoplasm) forming the Cvt vesicle.