Ubiquitination in the regulation of autophagy

Abstract

Autophagy, an efficient and effective approach to clear rapidly damaged organelles, macromolecules, and other harmful cellular components, enables the recycling of nutrient materials and supply of nutrients to maintain cellular homeostasis. Ubiquitination plays an important regulatory role in autophagy. This paper summarizes the most recent progress in ubiquitin modification in various stages of autophagy, including initiation, elongation, and termination. Moreover, this paper shows that ubiquitination is an important way through which selective autophagy achieves substrate specificity. Furthermore, we note the distinction between monoubiquitination and polyubiquitination in the regulation of autophagy. Compared with monoubiquitination, polyubiquitination is a more common strategy to regulate the activity of the autophagy molecular machinery. In addition, the role of ubiquitination in the closure and fusion of autophagosomes warrants further study. This article not only clarifies the regulatory mechanism of autophagy but also contributes to a deeper understanding of the importance of ubiquitination modification.

Keywords: autophagy molecule machine; monoubiquitination; polyubiquitination; selective autophagy.

Figure 1

The types and stages of autophagy (A) Three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. (B) The stages of autophagy are divided into six steps: initiation, nucleation, elongation, closure, fusion, and degradation.

Figure 2

Ubiquitination diversity (A) Mono-ubiquitination occurs at a single site or multiple sites on substrates. (B) Polyubiquitination: homo-ubiquitination and hetero-ubiquitination. Homo-ubiquitination is the process by which ubiquitin is linked to its same lysine residue or methionine residue. Ubiquitin is linked to different lysine residues, which is the definition of hetero-ubiquitination.

Figure 3

Ubiquitination is involved in the regulation of autophagy (A) The K48-linked ubiquitin chain destabilizes ULK1 to terminate autophagy, while the K63-linked ubiquitin chain triggers ULK1 activity to promote autophagy. (B) Beclin-1 decorated with the K63-linked ubiquitin chain promotes autophagy. The modification is balanced by ubiquitin ligases and de-ubiquitination enzymes. (C) During the formation of the autophagosome, LC3 is tagged with a mono-ubiquitination signal, while WIPI2 is polyubiquitinated. (D) During the assembly of cargo, p62 is labeled with K63-linked ubiquitin chains at different sites. (E) During autophagosome closure, the core component of the ESCRT complex, TSG101 is mono- or poly-ubiquitinated to cause degradation. (F) Small GTPase is likely to be linked to different polyubiquitin chains, which inhibits the fusion between autophagosome and lysosome. Syntaxin 17 with polyubiquitin chains promotes the fusion of the autophagosome and lysosome.

Figure 4

Ubiquitination in selective autophagy (A) During mitophagy, damaged mitochondria can be linked to the autophagy cargo receptor p62 when the ubiquitin ligase Parkin is phosphorylated to be activated by PINK1. (B) Oligomerized proteins with K63-linked ubiquitin chains are linked to p62 and then engulfed by the autophagosome; this is termed aggrephagy. (C) Peroxisome protein PMP70/PEX5 is tagged with mono-ubiquitin by the ubiquitin ligase PEX2, and this decoration is readily recognized by the autophagy cargo receptor NBR1 during pexophagy. (D) Ribosomes are recruited to the cargo receptors for degradation via autophagy after the 60s subunit of the ribosome is ubiquitinated. (E) Upon starvation, ubiquitinated proteasomes are linked to cargo receptor p62, and then interact with the autophagic membrane via the conjunct protein LC3. (F) During infection, bacteria are decorated with polyubiquitin chains and engulfed by the autophagic membrane via cargo receptor p62.