LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity
LHPP, a risk factor for major depressive disorder, regulates stress-induced depression-like behaviors through its histidine phosphatase activity
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DOI：
10.1038/s41380-022-01893-0
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发表时间：
2022-12
影响因子：
11
通讯作者：
Dong Lin;Luhui Li;Wenbing Chen;Jiang Chen;Dongyan Ren;Zhi-Heng Zheng;Changqin Zhao;Yanzi Zhong-Yanzi
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文献类型：
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作者：
Dong Lin;Luhui Li;Wenbing Chen;Jiang Chen;Dongyan Ren;Zhi-Heng Zheng;Changqin Zhao;Yanzi Zhong-Yanzi
组氨酸磷酸化（pHis）发生在底物蛋白的组氨酸上，是一种隐藏的磷酸化蛋白质组，在哺乳动物中很少被表征。LHPP （phospholysine phosphohistidine inorganic焦磷酸盐磷酸酶）是一种组氨酸磷酸酶，其编码基因最近被发现是重度抑郁症（MDD）的易感基因。然而，人们对LHPP或pHis是如何导致抑郁症的知之甚少。通过遗传学、行为学和电生理学的综合方法，我们观察到内侧前额叶皮层（mPFC）的LHPP在预防应激诱导的抑郁样行为中至关重要。LHPP基因缺失本身并不影响小鼠的抑郁样行为，但它显著增强了小鼠在慢性社会失败应激（CSDS）下的行为。这种增强可以通过mPFC中LHPP的局部缺失来概括。相比之下，mPFC中LHPP的过表达增加了小鼠对CSDS的恢复能力，这表明mPFC LHPP在应激性抑郁中起着关键作用。我们进一步发现，LHPP缺乏增加了皮层中组氨酸激酶（NME1/2）和全局pHis的水平，并减少了CSDS时mPFC中谷氨酸能的传递。NME1/2作为LHPP的底物，LHPP内的天冬氨酸17 （D17）、苏氨酸54 （T54）或D214残基对其磷酸酶活性至关重要。最后，将LHPP（而非LHPP磷酸酶死亡突变体）重新引入LHPP缺陷小鼠的mPFC，逆转了它们在CSDS时的行为和突触缺陷。总之，这些结果证明了LHPP在调节压力相关抑郁症中的关键作用，并为MDD的发病机制提供了新的见解。
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.