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Role of sestrins in metabolic and aging-related diseases

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Abstract

Sestrins are a type of highly conserved stress-inducing protein that has antioxidant and mTORC1 inhibitory functions. Metabolic dysfunction and aging are the main risk factors for development of human diseases, such as diabetes, neurodegenerative diseases, and cancer. Sestrins have important roles in regulating glucose and lipid metabolism, anti-tumor functions, and aging by inhibiting the reactive oxygen species and mechanistic target of rapamycin complex 1 pathways. In this review, the structure and biological functions of sestrins are summarized, and how sestrins are activated and contribute to regulation of the downstream signal pathways of metabolic and aging-related diseases are discussed in detail with the goal of providing new ideas and therapeutic targets for the treatment of related diseases.

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Abbreviations

AMPK:

Adenosine 5′-monophosphate (AMP)-activated protein kinase

AREs:

Antioxidant response elements

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

ATM:

Ataxia-telangiectasia mutated

ATR:

Ataxia-telangiectasia and RAD3-related

C/EBPβ:

CCAAT/enhancer-binding protein beta

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinases

FoxO1:

Forkhead box protein O1

FoxO3:

Forkhead box protein O3

GATOR:

GTPase-activating protein (GAP) activity towards rags

GLI2:

Glioma-associated oncogene family zinc finger 2

GRB10:

Growth factor receptor binding protein 10

HIF l:

Hypoxia-inducible factor l

IGF1:

Insulin-like growth factor 1

IRE1:

Inositol-requiring enzyme 1

JNK:

C-Jun N-terminal kinase

KEAP1:

Kelch-like epichlorohydrin-associated protein 1

MAPK:

Mitogen-activated protein kinases

mTORC1:

Mechanistic target of rapamycin complex 1

mTORC2:

Mechanistic target of rapamycin complex 2

NLRP3:

NOD-like receptor family, pyrin domain containing protein 3

NMDAR:

N-methyl-D aspartate receptor

Nrf2:

Nuclear factor erythroid 2-related factor 2

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

PI3K:

Phosphatidylinositol 3-kinase

PRX:

Peroxiredoxin

PTEN:

Phosphatase and tensin homology deleted on chromosome ten

Rags:

Ras-related GTPase

Rheb:

Ras homolog enriched in brain

ROS:

Reactive oxygen species

Smad3:

Drosophila mothers against decapentaplegic homolog 3

SQSTM1:

Sequestosome 1

SREBP:

Sterol regulatory element binding protein

SRX:

Sulfiredoxin

S6K1:

Ribosomal protein S6 kinase, polypeptide 1

TGF-β:

Transforming growth factor beta

TRX1:

Thioredoxin-1

TSC1:

Tuberous sclerosis complex 1

TSC2:

Tuberous sclerosis complex 2

ULK1:

Unc-51 like autophagy activating kinase 1

XBP1:

X-box binding protein

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Acknowledgements

This study was supported in part by the following funding sources: National Natural Science Foundation of China (82100632, 82170325), Sichuan Province science and technology projects (2021YFH0148) and Science and Technology Strategic Cooperation Programs of Luzhou Municipal People’s Government and Southwest Medical University (2021LZXNYD-J09, 2019LZXNYDJ30). Cartoon images used in Graphical abstract were obtained from Scidraw.io.

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  1. Huan Fang and Xiaomin Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, China

    Huan Fang, Xiaomin Shi & Xiaolin Zhong

  2. Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, China

    Juyi Wan

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  1. Huan Fang
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  2. Xiaomin Shi
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  3. Juyi Wan
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  4. Xiaolin Zhong
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Contributions

XZ provided direction and guidance throughout the preparation of the manuscript. HF performed the literature search and wrote the original manuscript. YW provided constructive suggestions and made significant revisions to the manuscript. XS helped revise the manuscript. All authors read and approved the final manuscript.

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Correspondence to Juyi Wan or Xiaolin Zhong.

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Fang, H., Shi, X., Wan, J. et al. Role of sestrins in metabolic and aging-related diseases. Biogerontology 25, 9–22 (2024). https://doi.org/10.1007/s10522-023-10053-y

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