Rbm12, or RNA-binding motif protein 12, is an RNA-binding protein located in the exon junction complex (EJC). It can bind to specific RNA via its RNA recognition motifs (RRMs), influencing RNA-related processes like modification, splicing, etc. Rbm12 is involved in multiple biological pathways, such as the G protein-coupled receptor/cyclic AMP/protein kinase A (GPCR/cAMP/PKA) signaling axis, and is of great biological importance as it relates to various diseases [4,6].

In hepatocellular carcinoma (HCC), high Rbm12 expression promotes cell propagation, migration, invasion, and inhibits apoptosis. It can also induce the EMT process by secreting TGF-β1. Mechanistically, miR-497-5p suppresses Rbm12 expression and tumor growth, and CPNE1, a downstream gene of Rbm12, is essential for Rbm12-promoted liver cancer progression [1]. Additionally, Rbm12 drives PD-L1-mediated immune evasion in HCC by enhancing JAK1 mRNA translation [2]. In bioinformatics-based studies, high Rbm12 expression in HCC tissues is associated with poor prognosis, and hypomethylation may lead to increased Rbm12 expression. Rbm12 is also linked to immune cell infiltration in HCC [3].

In the context of psychosis, Rbm12 is a high-penetrance risk factor. Loss of Rbm12 in HEK293 cells and human iPSC-derived neurons leads to hyperactive cAMP production, increased PKA activity, and altered neuronal transcriptional responses to GPCR stimulation. Truncating mutations in Rbm12 are associated with psychosis in Icelandic and Finnish families [4,6,7].

In the regulation of fetal hemoglobin (HbF), depletion of Rbm12 in erythroid cells from sickle cell disease (SCD) patients induces HbF expression with minimal impact on cell maturation, suggesting Rbm12 as a novel HbF suppressor [5].

In the regulation of mitophagy, knockdown of Rbm12 leads to altered splicing outcomes and elevated levels of BECN1-S, which upregulates mitophagy [8].

In conclusion, Rbm12 plays crucial roles in multiple biological processes and disease conditions. In HCC, it promotes tumor progression and immune evasion. In psychosis, it is a risk factor related to abnormal GPCR/cAMP signaling. In SCD, it regulates HbF expression. The study of Rbm12 in these models helps in understanding the underlying disease mechanisms, potentially providing new therapeutic targets.

References:

1. Gao, Cheng, Zhu, Renfei, Shen, Jianbo, She, YongJun, Chen, Zhong. 2023. RBM12 regulates the progression of hepatocellular cancer via miR-497-5p/CPNE1 Axis. In Environmental research, 239, 117203. doi:10.1016/j.envres.2023.117203. https://pubmed.ncbi.nlm.nih.gov/37793588/

2. Han, Hexu, Shi, Qian, Zhang, Yue, Guo, Huimin, Wang, Qiang. 2024. RBM12 drives PD-L1-mediated immune evasion in hepatocellular carcinoma by increasing JAK1 mRNA translation. In Oncogene, 43, 3062-3077. doi:10.1038/s41388-024-03140-y. https://pubmed.ncbi.nlm.nih.gov/39187545/

3. Gao, Cheng, Shen, Jianbo, Chen, Weipeng, Zhu, Renfei, Chen, Zhong. . Increased RBM12 expression predicts poor prognosis in hepatocellular carcinoma based on bioinformatics. In Journal of gastrointestinal oncology, 12, 1905-1926. doi:10.21037/jgo-21-390. https://pubmed.ncbi.nlm.nih.gov/34532138/

4. Semesta, Khairunnisa M, Garces, Angelica, Tsvetanova, Nikoleta G. 2023. The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction. In The Journal of biological chemistry, 299, 105133. doi:10.1016/j.jbc.2023.105133. https://pubmed.ncbi.nlm.nih.gov/37543364/

5. Wakabayashi, Aoi, Kihiu, Maryanne, Sharma, Malini, Shi, Junwei, Blobel, Gerd A. . Identification and characterization of RBM12 as a novel regulator of fetal hemoglobin expression. In Blood advances, 6, 5956-5968. doi:10.1182/bloodadvances.2022007904. https://pubmed.ncbi.nlm.nih.gov/35622975/

6. Semesta, Khairunnisa M, Garces, Angelica, Tsvetanova, Nikoleta G. 2023. The psychosis risk factor RBM12 encodes a novel repressor of GPCR/cAMP signal transduction. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.01.12.523776. https://pubmed.ncbi.nlm.nih.gov/36711667/

7. Steinberg, Stacy, Gudmundsdottir, Steinunn, Sveinbjornsson, Gardar, Stefansson, Hreinn, Stefansson, Kari. 2017. Truncating mutations in RBM12 are associated with psychosis. In Nature genetics, 49, 1251-1254. doi:10.1038/ng.3894. https://pubmed.ncbi.nlm.nih.gov/28628109/

8. Wang, Jiahe, Fan, Yi, Luo, Guowen, Zhang, Zhenwei, Zhou, Chenchen. 2025. Nuclear Condensates of WW Domain-Containing Adaptor With Coiled-Coil Regulate Mitophagy via Alternative Splicing. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12, e2406759. doi:10.1002/advs.202406759. https://pubmed.ncbi.nlm.nih.gov/39840526/