Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

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Abstract

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.

Graphical abstract

This review elucidates the autophagic and non-autophagic roles of Beclin-1 in regulating cancer-related progresses and further summarizes the therapeutic potential of Beclin-1-regulating strategies for cancer treatment.

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Highly accurate protein structure prediction with AlphaFold

John Jumper, Richard Evans, Alexander Pritzel … (2021)

Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1 – 4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6 , 7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10 – 14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm. AlphaFold predicts protein structures with an accuracy competitive with experimental structures in the majority of cases using a novel deep learning architecture.

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AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

Joungmok Kim, Mondira Kundu, Benoit Viollet … (2011)

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

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The role of Atg proteins in autophagosome formation.

Noboru Mizushima, Tamotsu Yoshimori, Yoshinori Ohsumi (2011)

Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.

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Author and article information

Contributors

Bo Liu

Gu He

Journal

Journal ID (nlm-ta): Acta Pharm Sin B

Journal ID (iso-abbrev): Acta Pharm Sin B

Title: Acta Pharmaceutica Sinica. B

Publisher: Elsevier

ISSN (Print): 2211-3835

ISSN (Electronic): 2211-3843

Publication date PMC-release: 12 August 2023

Publication date (Print): December 2023

Publication date (Electronic): 12 August 2023

Volume: 13

Issue: 12

Pages: 4688-4714

Affiliations

[a ]Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

[b ]Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease Related Molecular Network, Chengdu 610041, China

Author notes

[∗ ]Corresponding authors. Tel.: +86 28 85503817; fax: +86 28 85164063. liubo2400@ 123456163.com hegu@ 123456scu.edu.cn

[†]

These authors made equal contributions to this work.

Article

Publisher Item ID: S2211-3835(23)00304-0

DOI: 10.1016/j.apsb.2023.08.008

PMC ID: 10692397

PubMed ID: 38045051

SO-VID: 66a52a03-46a5-45fd-96c0-8c4306a2c738

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 3 May 2023

Date revision received : 5 July 2023

Date accepted : 2 August 2023

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Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

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Bulletin Of Medical And Biological Research

Most cited references 306

Highly accurate protein structure prediction with AlphaFold

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

The role of Atg proteins in autophagosome formation.

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Cited by 8

Most referenced authors 3,970