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Review
. 2023 Aug 2;11(5):101060.
doi: 10.1016/j.gendis.2023.06.029. eCollection 2024 Sep.

Protein lysine crotonylation in cellular processions and disease associations

Hongling Zhao  1 , Yang Han  1 , Pingkun Zhou  1 , Hua Guan  1 , Shanshan Gao  1
Affiliations
Review

Protein lysine crotonylation in cellular processions and disease associations

Hongling Zhao et al. Genes Dis. .

Abstract

Protein lysine crotonylation (Kcr) is one conserved form of posttranslational modifications of proteins, which plays an important role in a series of cellular physiological and pathological processes. Lysine ε-amino groups are the primary sites of such modification, resulting in four-carbon planar lysine crotonylation that is structurally and functionally distinct from the acetylation of these residues. High levels of Kcr modifications have been identified on both histone and non-histone proteins. The present review offers an update on the research progression regarding protein Kcr modifications in biomedical contexts and provides a discussion of the mechanisms whereby Kcr modification governs a range of biological processes. In addition, given the importance of protein Kcr modification in disease onset and progression, the potential viability of Kcr regulators as therapeutic targets is elucidated.

Keywords: Cell biology; Disease; Lysine crotonylation; Posttranslational modification; Therapeutic target.

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Figures

Fig. 1
Figure 1
Chemical structures of protein lysine acylations. Acylation types are classified into two groups, HKcr group and NHKcr group, based on substrates of histone or non-histone proteins.
Fig. 2
Figure 2
The regulatory factors of crotonyaltion. Readers, writers (crotonyltransferase, HCT), and erasers (decrotonylase, HDCR) in histone and non-histone proteins are shown in this review. The readers are recruited by protein Kcr. Protein Kcr is balanced by HCT and HDCR in vitro and in vivo.
Fig. 3
Figure 3
The function of histone and non-histone proteins Kcr in DNA damage and repair. (A) Ionizing radiation (IR), ultraviolet radiation (UV), or etoposide (VP16) decreases the levels of H3K9cr; during this process, HDACs are the major HDCR in U2OS cells. (B) The role of RPA1 Kcr in camptothecin (CPT)-induced DSB of DNA. CDYL negatively regulated Kcr of RPA1 at K88, K379, and K595 sites, which were involved in DNA damage. (C) CDYL1 crotonyl-CoA hydratase activity counteracts Kcr and H3K9cr at DSB sites, which triggers the eviction of the transcription elongation factor ENL and fosters transcriptional silencing.
Fig. 4
Figure 4
The mechanism of Kcr involves in cell cycle progression. (A) NaCr increases the Kcr of histone H3 and influences the phosphorylation of histone H3 at the Ser10 site in a dose-dependent manner, which is the mark of G2/M phase cells. NaCr treatment decreases the amount of S phase cells and raises cells in the G2 phase. (B) The role of EB1 Kcr in spindle positioning and orientation during mitosis. TIP60 controls the dynamic Kcr level of EB1 to carry out fine-tuning of mitotic spindle positioning and to facilitate accurate sister chromatids separation.
Fig. 5
Figure 5
Non-histone and histone Kcr-associated diseases. The whole level of crotonylation is down-regulated in stomach, liver, and kidney cancers and up-regulated in lung, pancreatic, esophageal, thyroid, and colon cancers; BTBR T Itpr3tf/J (BTBR) mice present with higher global Kcr levels in the cerebral cortex, and CDYL-mediated reductions in histone Kcr modification to influence stress-induced depression. Functional enrichment analysis of up-regulated crotonylated proteins in samples of COPD patients with type II RF reveals that they enriched a range of mechanisms related to the pathogenesis of COPD and type II RF. The down-regulation of ECHS1 results in pronounced increases in the levels of NFATc3, H3K18cr, and H2BK12cr, promoting hypertrophic neonatal cardiomyocyte growth. Crotonlyation has the potential to impact a range of renal diseases, such as AKI, immunoglobulin A nephropathy, and hemodialysis. Histone Kcr modification at the site of the HIV LTR can regulate its transcriptional activity to facilitate the establishment of HIV latency. PHF5A K25 deKcr in senescent fibroblast cells can drive more rapid senescence, and global protein Kcr expression levels underscore a link between Kcr modifications and murine ovarian aging. The lncRNA EPB41L4A-AS1 can control H3K27 Kcr at the GLUT4 promoter to suppress GLUT4 expression.
Fig. 6
Figure 6
Regulation and functions of non-histone and histone Kcr. Kcr has been identified on lysine residues in histone and non-histone proteins. Protein Kcr was catalyzed by transferases (HCT) and decrotonylases (HDACR). Furthermore, Kcr acts as docking marks to recruit readers. The mechanism of Kcr involves many biological processes, such as DNA damage repair, gene transcription, and cell cycle. Protein Kcr plays roles in many diseases, such as cancer, neurological disorders, and cardiovascular disease.
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