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LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity

Molecular Psychiatry volume 28, pages 908–918 (2023)Cite this article

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Abstract

Histidine phosphorylation (pHis), occurring on the histidine of substrate proteins, is a hidden phosphoproteome that is poorly characterized in mammals. LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) is one of the histidine phosphatases and its encoding gene was recently identified as a susceptibility gene for major depressive disorder (MDD). However, little is known about how LHPP or pHis contributes to depression. Here, by using integrative approaches of genetics, behavior and electrophysiology, we observed that LHPP in the medial prefrontal cortex (mPFC) was essential in preventing stress-induced depression-like behaviors. While genetic deletion of LHPP per se failed to affect the mice’s depression-like behaviors, it markedly augmented the behaviors upon chronic social defeat stress (CSDS). This augmentation could be recapitulated by the local deletion of LHPP in mPFC. By contrast, overexpressing LHPP in mPFC increased the mice’s resilience against CSDS, suggesting a critical role of mPFC LHPP in stress-induced depression. We further found that LHPP deficiency increased the levels of histidine kinases (NME1/2) and global pHis in the cortex, and decreased glutamatergic transmission in mPFC upon CSDS. NME1/2 served as substrates of LHPP, with the Aspartic acid 17 (D17), Threonine 54 (T54), or D214 residue within LHPP being critical for its phosphatase activity. Finally, reintroducing LHPP, but not LHPP phosphatase-dead mutants, into the mPFC of LHPP-deficient mice reversed their behavioral and synaptic deficits upon CSDS. Together, these results demonstrate a critical role of LHPP in regulating stress-related depression and provide novel insight into the pathogenesis of MDD.

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Fig. 1: LHPP deficiency induces depression-like behaviors in mice upon CSDS.
Fig. 2: LHPP in mPFC is essential for regulating CSDS-induced depression.
Fig. 3: LHPP dephosphorylates NME1/2.
Fig. 4: LHPP phosphatase activity in mPFC is essential for preventing CSDS-induced depression.
Fig. 5: LHPP phosphatase activity in mPFC is essential for restoring decreased glutamatergic transmission in NEX-Lhppf/f mice upon CSDS.

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Acknowledgements

We thank Dr. Yu-Qiang Ding (Fudan University) for providing the NEX-Cre mice, Piliang Hao and Chengqian Zhang for assistance with mass spectrometry equipment at the Biological Mass Spectrometry Core Facility (ShanghaiTech University). This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82125010 and 81930032 [to B-XP], 82271558 and 31771142 [to EF], 31660268 [to XL], 32100822 [to W-BC]), the China Postdoctoral Science Foundation (2021M700061, W-BC) and the National Key R&D Program of China (2021ZD0202704, B-XP).

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  1. These authors contributed equally: Dong Lin, Luhui Li, Wen-Bing Chen.

Authors and Affiliations

  1. School of Life Sciences, Nanchang University, Nanchang, 330031, China

    Dong Lin, Luhui Li, Dongyan Ren, Zhi-Heng Zheng, Changqin Zhao, Yanzi Zhong, Suqi Zou, Xinsheng Lai, Bing-Xing Pan & Erkang Fei

  2. Institute of Life Science, Nanchang University, Nanchang, 330031, China

    Dong Lin, Luhui Li, Wen-Bing Chen, Jiang Chen, Dongyan Ren, Zhi-Heng Zheng, Changqin Zhao, Yanzi Zhong, Bin Luo, Hongyang Jing, Peng Chen, Suqi Zou, Xinsheng Lai, Bing-Xing Pan & Erkang Fei

  3. School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China

    Tian Zhou

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Ning Ding & Lei Li

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Contributions

EF and DL conceived and designed the research project. DL, LuhuiL, W-BC, JC, Z-HZ, CZ, YZ, and EF performed experiments and collected data. ND and LeiL performed proteomic experiments and collected data. DL, W-BC, DR, TZ, SZ, B-XP and EF analyzed data. DL and W-BC prepared manuscript figures. EF, DL, and B-XP wrote the manuscript. BL, HJ, PC, SZ, XL, and TZ provided technical and intellectual support. All authors provided critical reviews of results and approved the manuscript.

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Correspondence to Bing-Xing Pan or Erkang Fei.

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Lin, D., Li, L., Chen, WB. et al. LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity. Mol Psychiatry 28, 908–918 (2023). https://doi.org/10.1038/s41380-022-01893-0

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