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Chemical Biology of Autophagy-Related Proteins With Posttranslational Modifications: From Chemical Synthesis to Biological Applications.

ABSTRACT: Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved lysosomal degradation pathway in all eukaryotic cells, which is critical for maintaining cell homeostasis. A series of autophagy-related (ATG) proteins are involved in the regulation of autophagy. The activities of ATG proteins are mainly modulated by posttranslational modifications (PTMs), such as phosphorylation, lipidation, acetylation, ubiquitination, and sumoylation. To tackle molecular mechanisms of autophagy, more and more researches are focusing on the roles of PTMs in regulation of the activity of ATG proteins and autophagy process. The protein ligation techniques have emerged as powerful tools for the chemical engineering of proteins with PTMs, and provided effective methods to elucidate the molecular mechanism and physiological significance of PTMs. Recently, several ATG proteins with PTM were prepared by protein ligation techniques such as native chemical ligation (NCL), expressed protein ligation (EPL), peptide hydrazide-based NCL, and Sortase A-mediated ligation (SML). More importantly, the synthesized ATG proteins are successfully used to probe the mechanism of autophagy. In this review, we summarize protein ligation techniques for the preparation of ATG proteins with PTMs. In addition, we highlight the biological applications of synthetic ATG proteins to probe the autophagy mechanism.

SUBMITTER: Luo Y

PROVIDER: S-EPMC7145982 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Chemical Biology of Autophagy-Related Proteins With Posttranslational Modifications: From Chemical Synthesis to Biological Applications.

Luo Yu Y Jiang Chen C Yu Lihua L Yang Aimin A

Frontiers in chemistry 20200403

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved lysosomal degradation pathway in all eukaryotic cells, which is critical for maintaining cell homeostasis. A series of autophagy-related (ATG) proteins are involved in the regulation of autophagy. The activities of ATG proteins are mainly modulated by posttranslational modifications (PTMs), such as phosphorylation, lipidation, acetylation, ubiquitination, and sumoylation. To tackle molecular mechanisms of autophag ...[more]

PMID: 32309274

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Project description:BackgroundDue to the unique nature of spermatozoa, which are transcriptionally and translationally silent, the regulation of capacitation is based on the formation of posttranslational modifications of proteins (PTMs). However, the interactions between different types of PTMs during the capacitation remain unclear. Therefore, we aimed to unravel the PTM-based regulation of sperm capacitation by considering the relationship between tyrosine phosphorylation and reversible oxidative PTMs (oxPTMs), i.e., S-nitrosylation and S-glutathionylation. Since reversible oxPTMs may be closely related to peroxyredoxin (PRDX) activity, the second aim was to verify the role of PRDXs in the PTM-based regulation of capacitation.MethodsCryopreserved bull sperm were capacitated in vitro with or without PRDX inhibitor. Qualitative parameters of sperm and symptoms characteristic of capacitation were analyzed. Posttranslational protein modifications (S-nitrosylation, S-glutathionylation, tyrosine phosphorylation) were investigated at the cellular level (flow cytometry, fluorescence microscopy) and at the proteomic level (fluorescent gel-based proteomic approach).ResultsZona-pellucida binding proteins (ACRBP, SPAM1, ZAN, ZPBP1 and IZUMO4) were particularly rich in reversible oxPTMs. Moreover, numerous flagellar proteins were associated with all analyzed types of PTMs, which indicates that the direction of posttranslational modifications was integrated. Inhibition of PRDX activity during capacitation caused an increase in S-nitrosylation and S-glutathionylation and a decrease in tyrosine phosphorylation. Inhibition of PRDXs caused GAPDHS to undergo S-glutathionylation and the GSTO2 and SOD2 enzymes to undergo denitrosylation. Moreover, PRDX inhibition caused the AKAP proteins to be dephosphorylated.ConclusionsOur research provides evidence that crosstalk occurs between tyrosine phosphorylation and reversible oxPTMs during bull sperm capacitation. This study demonstrates that capacitation triggers S-nitrosylation and S-glutathionylation (and reverse reactions) of zona-pellucida binding proteins, which may be a new important mechanism that determines the interaction between sperms and oocytes. Moreover, TCA-related and flagellar proteins, which are particularly rich in PTMs, may play a key role in sperm capacitation. We propose that the deglutathionylation of ODFs and IZUMO4 proteins is a new hallmark of bull sperm capacitation. The obtained results indicate a relationship between PRDX activity and protein phosphorylation, S-glutathionylation and S-nitrosylation. The activity of PRDXs may be crucial for maintaining redox balance and for providing proper PKA-mediated protein phosphorylation during capacitation. Video Abstract.

Dataset Information

Chemical Biology of Autophagy-Related Proteins With Posttranslational Modifications: From Chemical Synthesis to Biological Applications.

Publications

Chemical Biology of Autophagy-Related Proteins With Posttranslational Modifications: From Chemical Synthesis to Biological Applications.

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