SIRT7-Induced PHF5A Decrotonylation Regulates Aging Progress Through Alternative Splicing-Mediated Downregulation of CDK2.

Ai Qing Yu,Xing Min Han,Hai Yan Ma,Yi Min Hu,Li Qun Yuan,Zhi Xiao Wang,Jie Wang,Shi Tao Jiang,Li Ming Tan

doi:10.3389/fcell.2021.710479

Abstract

Dysregulation of protein posttranslational modification (PTM) can lead to a variety of pathological processes, such as abnormal sperm development, malignant tumorigenesis, depression, and aging process. SIRT7 is a NAD+-dependent protein deacetylase. Besides known deacetylation, SIRT7 may also have the capacity to remove other acylation. However, the roles of SIRT7-induced other deacylation in aging are still largely unknown. Here, we found that the expression of SIRT7 was significantly increased in senescent fibroblasts and aged tissues. Knockdown or overexpression of SIRT7 can inhibit or promote fibroblast senescence. Knockdown of SIRT7 led to increased pan-lysine crotonylation (Kcr) levels in senescent fibroblasts. Using modern mass spectrometry (MS) technology, we identified 5,149 Kcr sites across 1,541 proteins in senescent fibroblasts, and providing the largest crotonylome dataset to date in senescent cells. Specifically, among the identified proteins, we found SIRT7 decrotonylated PHF5A, an alternative splicing (AS) factor, at K25. Decrotonylation of PHF5A K25 contributed to decreased CDK2 expression by retained intron (RI)-induced abnormal AS, thereby accelerating fibroblast senescence, and supporting a key role of PHF5A K25 decrotonylation in aging. Collectively, our data revealed the molecular mechanism of SIRT7-induced k25 decrotonylation of PHF5A regulating aging and provide new ideas and molecular targets for drug intervention in cellular aging and the treatment of aging-related diseases, and indicating that protein crotonylation has important implications in the regulation of aging progress.

Highlights

In eukaryotic cells, protein posttranslational modification (PTM) achieves rapid functional adaptation to various intracellular and external signals by regulating enzyme activity, and protein stability
We found that the expression levels of SIRT7 mRNA and protein were significantly elevated in replicative senescent fibroblasts, and premature senescent fibroblasts compared to young fibroblasts or corresponding control groups (Figures 1A,B)
In eukaryotic cells, reversible histone PTMs are important in regulating gene expression to quickly adapt to changes in the internal and external environment of the cell (Liu et al, 2019)

Summary

Introduction

Protein posttranslational modification (PTM) achieves rapid functional adaptation to various intracellular and external signals by regulating enzyme activity, and protein stability. With the development of modern mass spectrometry (MS) technology, a series of short-chain lysine acylation modifications including lactylation, crotonylation, β-hydroxyisobutyrylation, succinylation, and other new acylation modifications have been discovered (Sabari et al, 2017; Zhang et al, 2019). These novel acylation modifications are similar to the well-known lysine acetylation modification structure. The sirtuin family includes seven Sir homologous proteins (SIRT1–7), which share a conserved NAD+-dependent catalytic core domain, located in different subcellular compartments, targeting different substrates and enzyme activity, and control various important biological processes, including energy metabolism, resistance to stress, genome stability, aging, and tumors (Kida and Goligorsky, 2016). Can SIRT7 mediate other deacylation modifications to regulate aging?

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Conclusion