The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction.
The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction.
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精神病危险因子 RBM12 编码一种新型 GPCR/cAMP 信号转导抑制因子。
DOI：
10.1101/2023.01.12.523776
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Tsvetanova,NikoletaG
中科院分区：
文献类型：
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作者：
Semesta,KhairunnisaM;Garces,Angelica;Tsvetanova,NikoletaG
RBM 12是家族性精神分裂症和精神病的高风险因子，但其确切的细胞功能及其所属的通路尚不清楚。我们利用两种互补模型，HEK 293细胞和人iPSC衍生的神经元，并将RBM 12描述为G蛋白偶联受体/cAMP/PKA（GPCR/cAMP/PKA）信号轴的新型抑制剂。我们确定RBM 12的丢失导致cAMP产生过度活跃和PKA活性增加以及对GPCR刺激的神经元转录反应改变。值得注意的是，cAMP和转录信号步骤受到离散RBM 12依赖性调节。我们进一步证明了与家族性精神病相关的两个RBM 12截短变体影响了这种相互作用，因为突变体无法挽救RBM 12缺失细胞中的GPCR/cAMP信号过度活跃。最后，我们提出了受损的信号表型的机制。与其作为RNA结合蛋白的活性一致，RBM 12的缺失导致基因表达改变，包括受体途径内具有确定意义的多种效应物的表达。具体而言，腺苷酸环化酶、磷酸二酯酶亚型和PKA调节和催化亚基的丰度受到RBM 12耗尽的影响。我们注意到，这些表达变化与过度活跃信号输出的整个范围完全一致。总之，目前的研究确定了RBM 12在GPCR-cAMP途径中以前未被认识到的作用，可以进一步探索作为该因子在神经元生理学和病理生理学中功能的初步分子机制。
RBM12is a high-penetrance risk factor for familial schizophrenia and psychosis, yet its precise cellular functions and the pathways to which it belongs are not known. We utilize two complementary models, HEK293 cells and human iPSC-derived neurons, and delineate RBM12 as a novel repressor of the G protein–coupled receptor/cAMP/PKA (GPCR/cAMP/PKA) signaling axis. We establish that loss of RBM12 leads to hyperactive cAMP production and increased PKA activity as well as altered neuronal transcriptional responses to GPCR stimulation. Notably, the cAMP and transcriptional signaling steps are subject to discrete RBM12-dependent regulation. We further demonstrate that the twoRBM12truncating variants linked to familial psychosis impact this interplay, as the mutants fail to rescue GPCR/cAMP signaling hyperactivity in cells depleted of RBM12. Lastly, we present a mechanism underlying the impaired signaling phenotypes. In agreement with its activity as an RNA-binding protein, loss of RBM12 leads to altered gene expression, including that of multiple effectors of established significance within the receptor pathway. Specifically, the abundance of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits is impacted by RBM12 depletion. We note that these expression changes are fully consistent with the entire gamut of hyperactive signaling outputs. In summary, the current study identifies a previously unappreciated role for RBM12 in the context of the GPCR–cAMP pathway that could be explored further as a tentative molecular mechanism underlying the functions of this factor in neuronal physiology and pathophysiology.