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. 2021 Jun 10;6(24):15782-15793.
doi: 10.1021/acsomega.1c01161. eCollection 2021 Jun 22.

Co-occurrence of Protein Crotonylation and 2-Hydroxyisobutyrylation in the Proteome of End-Stage Renal Disease

Jingjing Dong  1   2 , Yixi Li  1   2 , Fengping Zheng  2 , Wenbiao Chen  2 , Shaoying Huang  2 , Xianqing Zhou  3 , Kang Wang  2 , Wanxia Cai  2 , HaiPing Liu  4 , Lianghong Yin  1 , Qiang Li  5 , Donge Tang  2 , Yong Dai  2   3
Affiliations

Co-occurrence of Protein Crotonylation and 2-Hydroxyisobutyrylation in the Proteome of End-Stage Renal Disease

Jingjing Dong et al. ACS Omega. .

Abstract

End-stage renal disease (ESRD) is gradually becoming a major public healthcare burden worldwide. Post-translational modifications carrying epigenetic information play a crucial role in the pathogenesis of many chronic diseases. We performed lysine crotonylation (KCr) and lysine 2-hydroxyisobutyrylation (Khib) analyses with liquid chromatography-tandem mass spectrometry to obtain a comprehensive profile and reveal the specific pathogenesis of peripheral blood mononuclear cells in ESRD patients. 218 overlap proteins among differentially modified proteins (DMPs) of both 2-hydroxyisobutyrylation and crotonylation were identified. KEGG analysis enriched pathways of protein processing in endoplasmic reticulum (ER) and glycolysis/gluconeogenesis which is closely related with cell apoptosis. In Bip, a master regulator in the ER, eight sites were identified as having both KCr and Khib modifications. Five differentially KCr modification sites and three differentially Khib-modified sites were detected between ESRD patients and normal controls. Besides Bip, other proteins (GRP94, CNX, CRT, PDIs, GlcII, ERP57, Bap31, Hsp70, and Hsp90) happened both KCr and Khib modifications. Nine DMPs having both KCr and Khib modifications were related to the glycolysis/gluconeogenesis pathway containing two key regulatory enzymes of hexokinase-1 and pyruvate kinase. The two most abundant dual modification proteins were ENO1 and PGK1 with 15 sites and 8 sites, respectively. Lysine residue K228 with both KCr and Khib modifications in ENO1 was on its surface and made it accessible for p300 mediating dynamic modifications. Overall, we hypothesize that KCr and Khib comodifications may influence the number of immunocytes and further induce immune senescence in ESRD patients through the glycolysis/gluconeogenesis pathway and protein processing in the ER process, which may be a potential therapeutic direction in the future.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Qualitative analysis of lysine crotonylation and 2-hydroxyisobutyrylation between ESRD patients and normal controls. (a) Venn graph representing the overlap proteins modified by dual lysine crotonylation and 2-hydroxyisobutyrylation. (b) Venn graph showing the overlap modified sites between lysine crotonylation and 2-hydroxyisobutyrylation. (c) Subcellular location of the overlap DMPs of dual KCr and Khib. (d) Functional category of the overlap DMPs of dual KCr and Khib in GO terms.
Figure 2
Figure 2
GO enrichment analysis and KEGG pathway enrichment analysis of overlap DMPs of dual Kcr and Khib. (a) Cellular component in the GO enrichment analysis. (b) Molecular function in the GO enrichment analysis. (c) Biological process in the GO enrichment analysis. (d) KEGG analysis of overlap DMPs of dual Kcr and Khib.
Figure 3
Figure 3
PPI network analysis of DMPs was performed, and two most significant modules were yielded with MCODE. One hundred and eighty three proteins from 218 overlapped DMPs of dual Khib and KCr were fetched according to the standard of combined score ≥0.9. Module 1 named regulation of actin cytoskeleton (score = 14.5) was constructed with 41 nodes and 290 edges. Module 2 named vesicle-mediated transport (score = 7.538) was constructed with 14 nodes and 49 edges.
Figure 4
Figure 4
DMPs of dual Kcr and Khib in protein processing in the ER signal pathway. (a) PPI network of DMPs of dual Kcr and Khib enriched in protein processing in the ER pathway. (b) Number of modified sites of Kcr and Khib in the ER signal pathway. (c) Overview of DMPs of dual Kcr and Khib in the ER signal pathway. (d) Three-dimensional structure of Bip protein constructed using SWISS MODEL. Comodification happened in eight lysine sites in Bip in the same site of crotonylation and 2-hydroxyisobutyrylation, which are labeled yellow.
Figure 5
Figure 5
DMPs of dual Kcr and Khib in protein processing in the glycolysis/gluconeogenesis signal pathway. (a) PPI network of DMPs of dual Kcr and Khib enriched glycolysis/gluconeogenesis pathway. (b) Number of modified sites of Kcr and Khib in the glycolysis/gluconeogenesis pathway. (c) Overview of DMPs of dual Kcr and Khib in the glycolysis/gluconeogenesis signal pathway.
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