The participation of non-canonical autophagic proteins in the autophagy process and their potential as therapeutic targets

ABSTRACT

Introduction

Autophagy is a conserved catabolic process that helps recycle intracellular components to maintain homeostasis. The completion of autophagy requires the synergistic effect of multiple canonical autophagic proteins. Defects in autophagy machinery have been reported to promote diseases, rendering autophagy a bone fide health-modifying agent. However, the clinical implication of canonical pan-autophagic activators or inhibitors has often led to undesirable side effects, making it urgent to find a safer autophagy-related therapeutic target. The discovery of non-canonical autophagic proteins has been found to specifically affect the development of diseases without causing a universal impact on autophagy and has shed light on finding a safer way to utilize autophagy in the therapeutic context.

Areas covered

This review summarizes recently discovered non-canonical autophagic proteins, how these proteins influence autophagy, and their potential therapeutic role in the disease due to their interaction with autophagy.

Expert opinion

Several therapies have been studied thus far and continued research is needed to identify the potential that non-canonical autophagic proteins have for treating certain diseases. In the meantime, continue to uncover new non-canonical autophagic proteins and examine which are likely to have therapeutic implications.

KEYWORDS:

• Autophagy
• diseases
• therapeutic targets
• Non-canonical autophagic proteins

Article highlights

• Molecular mechanism and related signaling pathway that implicate the canonical autophagy machinery.

• Autophagy maintains nutrient and energy homeostasis, and its dysregulation results in the development of various diseases.

• Noncanonical autophagic proteins that participate in different stages of autophagy exhibit therapeutic potential in ameliorating various diseases.

• Nonsystemic stimulation or inhibition of autophagy could be an important strategy in the treatment of certain diseases.

This box summarizes key points contained in the article.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviation

AMBRA1: Activating molecule in BECN1-regulated autophagy protein 1; AMPK: AMP-activated protein kinase; ATG: Autophagy-related; AURKA: Aurora kinase A: BIRC6: Ubiquitin-like modifier-activating enzyme 6; CCL2: C–C motif chemokine 2; CDK: Cyclin-dependent kinase; CMA: Chaperone-mediated autophagy: CNOT2: CCR4-NOT transcription complex subunit 2; CQ: Chloroquine; CRBN: Cereblon; DDX53: DEAD-Box Helicase 53; DFCP1: Zinc-finger FYVE domain-containing protein 1; FIP200: Focal adhesion kinase family-interacting protein of 200 kDa; FOXM1: Forkhead box protein M1; GAPR-1: Golgi-associated plant pathogenesis-related protein 1; GSK3β: Glycogen synthase kinase 3β; HCQ: Hydroxychloroquine; HDAC4: Histone deacetylase 4; HS1BP3: HCLS1 binding protein 3; iPSCs: Induced pluripotent stem cells; KAT2B: Lysine acetyltransferase 2B; KLF2/4 Kruppel-like transcription factors 2/4; KLFs: Kruppel-like transcription factors; LC3: Light chain 3; Lys63: Lysine 63; MAPK: Mitogen-activated protein kinase: MCP-1: monocyte chemotactic protein 1; MK2/3: MAPK-activated protein kinase 2/3; mTOR: Mammalian target of rapamycin; mTORC1: mTOR complex1; mTORC2: mTOR complex2; NAD⁺: Nicotinamide adenine dinucleotide; NAMPT: Nicotinamide phosphoribosyl transferase; NLR: Nucleotide-binding and oligomerization domain-like receptor; NLRP4: NACHT, LRR, and PYD domains-containing protein 4; PCAF: P300/CBP-associated factor; PE: Phosphatidylethanolamine; PLK1: Polo-like kinase 1; POU5F1: POU domain, class 5, transcription factor 1; PRDX1: Peroxiredoxin 1; PtdIns3K-CI: Class III phosphoinositide 3-kinase complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; PtdIns4P: Phosphatidylinositol-4-phosphate; RAGE: Receptor for advanced glycation end products; RB1CC1: RB1-inducible coiled-coil protein 1; SIRT3: Sirtuin 3; SOX2: Sex determining region Y-box 2; SRY: Sex determining region Y; TMFR: Tumor necrosis factor receptor; TRAF6: TNFR-associated factor 6; Ub: Ubiquitin; UBA6: Ubiquitin-like modifier-activating enzyme 6; ULK1: Unc-51-like kinase 1; VAPA/B: Vesicle-associated membrane protein-associated proteins A/B; VPS34: Vacuolar protein sorting 34; WIPI: WD repeat domain phosphoinositide-interacting protein; WNK2: WNK lysine-deficient protein kinase 2; XRN1: 5’-3’ Exoribonuclease 1; αSNAP Soluble N-ethylmaleimide-sensitive factor attachment protein α.

Author contributions

The idea for the article was proposed by Peihua Luo, Qiaojun He, and Hao Yan; the literature search was done by Yiming Yin, Yourong Zhou, Zhifei Xu, Peihua Luo, and Xiaochun Yang; the draft of the manuscript was written by Yiming Yin, and Yourong Zhou; the revision work was carried out by Yourong Zhou, Xiaochun Yang, Zhifei Xu, Bo Yang, Qiaojun He, and Hao Yan. All authors read and approved the final manuscript.

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (Nos. 82173893 and 82104315).