Review
A Destiny for Degradation: Interplay between Cullin-RING E3 Ligases and Autophagy

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Highlights

  • Autophagy is a highly conserved catabolic process that depends on autophagosome fusion with lysosomes for degradation.

  • CRLs are the largest subfamily of RING E3 ligases and are responsible for ~20% of total protein degradation via the UPS.

  • CRLs have emerged as crucial regulators of autophagy by targeting ATGs and upstream regulators such as MTORC1.

  • Dysregulation of CRLs and autophagy is associated with human diseases such as cancer, neurodegenerative conditions, and cardiomyopathies.

Autophagy and the ubiquitin-proteasome system (UPS) are two major pathways for protein degradation. The cullin-RING E3 ligases (CRLs) are the largest E3 ligase family and have key biological functions in maintaining protein homeostasis. We provide an updated review of the interactions between CRLs and autophagy, focusing on the regulatory effects of CRLs on the core autophagy machinery that consists of several autophagy-related protein (ATG) complexes and their key upstream signaling pathways. The involvement of such functional interactions in health and disease is also discussed. Understanding the role of CRLs in autophagy is helpful for the development of therapeutic strategies for diseases in which CRLs and autophagy are dysregulated, such as cancer and neurodegenerative conditions.

Section snippets

Autophagy and Its Core Machineries

Autophagy is a highly conserved catabolic process in which cytosolic contents including protein aggregates and damaged organelles are engulfed into autophagosomes for lysosomal degradation. In mammals, autophagy can be categorized into three main types: macroautophagy (hereafter referred to as autophagy), microautophagy, and chaperone-mediated autophagy (CMA) [1].

In general, the process of autophagy consists of two consecutive stages: (i) autophagosome biogenesis, and (ii) autophagosome

Ubiquitination and the Cullin-RING E3 Ligase Family

Protein ubiquitination is mediated by the sequential action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s) [12]. Ubiquitin has seven lysine residues (K6, K11, K27, K29, K33, K48, K63) and one N-terminal methionine (M1) as ubiquitination sites [13]. K48-linked polyubiquitination is the best-studied form, and this generally controls protein degradation via UPS [14]. In addition, the ubiquitination process is reversible; in other words, the

The Regulatory Roles of CRLs in Autophagy

Among all the CRLs, most studies have focused on the function of CRL1s, CRL3s, and CRL4s in autophagy. Although a few studies reported a positive effect of CRLs on autophagy induction, most suggest that CRLs negatively regulate autophagy by targeting the autophagy core machinery and upstream signaling pathways (Figure 2). Consistent with this, inhibition of CRLs is able to effectively induce autophagy (Box 2).

Reciprocal Effects of Autophagy on CRLs

Most studies to date have focused on the regulation of CRLs on autophagy, and relatively little is known about the possible effects of the autophagic machinery and process on CRLs. The first example comes from a study showing that ATG16L1 is positively correlated with CUL3 neddylation and CUL3–KEAP1 (kelch-like ECH-associated protein 1) activity [71]. Although the specific mechanism underlying this effect has not been confirmed, this function of ATG16L1 is related to the inhibitory effects of

Involvement of CRLs-Regulated Autophagy in Human Disease

Dysregulation of autophagy is associated with a variety of human diseases. In the following sections we focus on the role of CRLs-regulated autophagy in some important human diseases including cancer, neurodegenerative disorders, and cardiomyopathy.

Concluding Remarks

Our summary of current work on CRLs and autophagy highlights the key role of CRLs in regulating autophagy by targeting MTORC1 and the core autophagy machinery, and emphasizes the involvement of dysregulated CRLs in various human diseases, including cancer, neurodegenerative disorders, and cardiomyopathy. Although significant progress has been made, many questions remain unresolved (see Outstanding Questions).

First, for macroautophagy, it will be important to study the role of CRLs in the

Acknowledgments

We apologize to colleagues whose work could not be cited owing to space limitations. This work was supported by research grants from the Singapore National Medical Research Council (NMRC/CIRG/1490/2018), the Singapore Ministry of Education (MOE2018-T2-1-060), and the University of Macau (SRG2020-00002-FHS and CPG2020-00029-FHS) to H-M.S.

Declaration of Interests

There are no interests to declare.

Glossary

ATG2–ATG9–WIPI complex
this complex plays an important role in securing the membrane source of the autophagosome, in mediating the binding of ATG proteins to membrane, and in phagophore–endoplasmic reticulum (ER) contact sites during phagophore expansion.
Cardiomyopathy
cardiac disorders associated with mechanical or electrical dysfunction that results in inappropriate ventricular dilatation or hypertrophy.
Death-associated protein kinase (DAPK)
a key kinase mediating the phosphorylation of BECN1 to

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