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The regulation of necroptosis by ubiquitylation

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Abstract

Necroptosis is a programmed necrosis that is mediated by receptor-interacting protein kinases RIPK1, RIPK3 and the mixed lineage kinase domain-like protein, MLKL. Necroptosis must be strictly regulated to maintain normal tissue homeostasis, and dysregulation of necroptosis leads to the development of various inflammatory, infectious, and degenerative diseases. Ubiquitylation is a widespread post-translational modification that is essential for balancing numerous physiological processes. Over the past decade, considerable progress has been made in the understanding of the role of ubiquitylation in regulating necroptosis. Here, we will discuss the regulatory functions of ubiquitylation in necroptosis signaling pathway. An enhanced understanding of the ubiquitylation enzymes and regulatory proteins in necroptotic signaling pathway will be exploited for the development of new therapeutic strategies for necroptosis-related diseases.

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Abbreviations

PCD:

Programmed cell death

DAMPs:

Damage-associated molecular patterns

Ub:

Ubiquitin

RIPK1:

Receptor-interacting protein kinase 1

RIPK3:

Receptor-interacting protein kinase 3

MLKL:

Mixed lineage kinase domain-like protein

TLR:

Toll-like receptor

TNFR1:

Tumor necrosis factor receptor type I

TRADD:

TNFR1-associated death domain protein

TRAF2:

TNF receptor-associated factor 2

cIAP:

Cellular inhibitor of apoptosis

FADD:

Fas-associated protein with death domain

CYLD:

Cylindromatosis

RHIMs:

RIP homotypic interaction motifs

ZBP1/DAI/DLM-1:

Z-DNA binding protein 1

ORAS:

OTULIN-related autoinflammatory syndrome

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Acknowledgements

This work was supported by grants from National Key Research and Development Program of China (No. 2021YFA1302200); National Natural Science Foundation of China (No.32170748 and No.81773075); the Key Research and Development Program of Ningxia (No.2022BFH02012); Shanghai Committee of Science and Technology (No. 21490714300 and No.18410720600) and Natural Science Foundation of Shanghai (No. 22ZR1448000).

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  1. Yiliang Chen and Wenqing Ren have contributed equally to this work.

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  1. Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Yiliang Chen, Wenqing Ren, Yuan He & Zhenyu Cai

  2. Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, Shanghai, 200120, China

    Yiliang Chen & Zhenyu Cai

  3. College of Pharmacy, Ningxia Medical University, Yinchuan, 750004, Ningxia Hui Autonomous Region, China

    Qingsong Wang & Zhenyu Cai

  4. Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China

    Dan Ma

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ZC had the idea for the review article; YC, WR, and QW performed the literature search; ZC, YC and WR drafted the manuscript; YH and DM critically revised the manuscript.

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Chen, Y., Ren, W., Wang, Q. et al. The regulation of necroptosis by ubiquitylation. Apoptosis 27, 668–684 (2022). https://doi.org/10.1007/s10495-022-01755-8

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