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Global phosphoproteomic analysis identified key kinases regulating male meiosis in mouse

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Abstract

Meiosis, a highly conserved process in organisms from fungi to mammals, is subjected to protein phosphorylation regulation. Due to the low abundance of phosphorylation, there is a lack of systemic characterization of phosphorylation regulation of meiosis in mammals. Using the phosphoproteomic approach, we profiled large-scale phosphoproteome of purified primary spermatocytes undergoing meiosis I, and identified 14,660 phosphorylation sites in 4419 phosphoproteins. Kinase-substrate phosphorylation network analysis followed by in vitro meiosis study showed that CDK9 was essential for meiosis progression to metaphase I and had enriched substrate phosphorylation sites in proteins involved in meiotic cell cycle. In addition, histones and epigenetic factors were found to be widely phosphorylated. Among those, HASPIN was found to be essential for male fertility. Haspin knockout led to misalignment of chromosomes, apoptosis of metaphase spermatocytes and a decreased number of sperm by deregulation of H3T3ph, chromosomal passenger complex (CPC) and spindle assembly checkpoint (SAC). The complicated protein phosphorylation and its important regulatory functions in meiosis indicated that in-depth studies of phosphorylation-mediated signaling could help us elucidate the mechanisms of meiosis.

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the iProX [66] partner repository with the dataset identifier PXD032089 (password: rp45).

Abbreviations

CDK:

Cyclin-dependent kinase

HASPIN:

Haploid germ cell-specific nuclear protein

H3T3:

Histone H3 threonine 3

CPC:

Chromosomal passenger complex

SAC:

Spindle assembly checkpoint

PP2A:

Serine-threonine protein phosphatase 2A

H2AX:

H2A Histone family, member X

SYCP3:

Synaptonemal complex protein 3

Ti4+-IMAC:

Titanium (IV) ion-immobilized metal affinity chromatography

LC–MS:

Liquid chromatography-mass spectrometry

REC8:

Meiotic recombination protein REC8 homolog

STAG3:

Cohesin subunit SA-3

SMC3:

Structural maintenance of chromosomes protein 3

SMC1:

Structural maintenance of chromosomes protein 1

KSPN:

Kinase-substrate phosphorylation network

iGPS:

GPS algorithm with the interaction filter

SRPK1:

Serine/arginine-rich protein-specific kinase 1

OA:

Okadaic acid

H3S10:

Histone H3 serine 10

H1FNT:

Testis-specific H1 histone

H1T:

Testicular H1 histone

HILS1:

Putative spermatid-specific linker histone H1-like protein

PcG:

Polycomb group

TUNEL:

TdT-mediated dUTP nick end labeling

Aurora B:

Serine/threonine-protein kinase aurora B

INCENP:

Inner centromere protein

BUBR1:

Bub1-related kinase

CENP-E:

Centromere-associated protein E

MCAK:

Mitotic centromere-associated kinesin

PTM:

Post-translational modification

DOT1L:

DOT1 like histone lysine methyltransferase

EZH1:

Enhancer of zeste homolog 1

VRK1:

Serine/threonine-protein kinase VRK1

KAT6B:

Histone acetyltransferase KAT6B

KDM7C:

Histone-lysine demethylase 7C

ARID5B:

AT-rich interactive domain-containing protein 5B

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Funding

This study was supported by the National Key R&D Program of China (2021YFC2700200), the Chinese National Natural Science Foundation (Grants Nos. 32071133, 82001611, 81971439), and the Fok Ying Tung Education Foundation (Grant No. 161037).

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Author notes

  1. Haojie Li, Hong Chen, Xiangzheng Zhang and Yaling Qi contributed equally to the work.

Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China

    Haojie Li, Hong Chen, Xiangzheng Zhang, Yaling Qi, Bing Wang, Yiqiang Cui, Jie Ren, Yichen Zhao, Yu Chen, Tianyu Zhu, Yue Wang, Liping Yao, Yueshuai Guo, Hui Zhu, Chenghao Situ & Xuejiang Guo

  2. School of Medicine, Southeast University, Nanjing, 210009, China

    Bing Wang

  3. Department of Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China

    Yan Li

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  1. Haojie Li
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  2. Hong Chen
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Contributions

XG, CS and YL conceived and designed the study. HL, HC, XZ, YQ, YW and LY performed most of the experiments. XZ and YG performed mass spectrometry experiments. BW conducted all of the mass spectrometry data analysis. YC constructed mouse models. JR, YZ, TZ, YC and HZ, analyzed the data. YL, CS and XG supervised the project. HL, YL, CS and XG wrote the manuscript, which was reviewed by all authors.

Corresponding authors

Correspondence to Yan Li, Chenghao Situ or Xuejiang Guo.

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Animal experiments were performed in compliance with ethical regulations of Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University (No: IACUC-1707017).

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Li, H., Chen, H., Zhang, X. et al. Global phosphoproteomic analysis identified key kinases regulating male meiosis in mouse. Cell. Mol. Life Sci. 79, 467 (2022). https://doi.org/10.1007/s00018-022-04507-8

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