Elp2, also known as Signal transducer and activator of transcription 3 (STAT3)-interacting protein 1 (StIP1), is the second major subunit of the highly conserved elongator complex, which is essential for transcription elongation, histone acetylation, and tRNA modification [2,5,7]. The elongator complex, with Elp2 as part of its catalytic core along with Elp1 and Elp3, is crucial for many cellular functions [2]. Elp2 is involved in the JAK-STAT3 pathway, which has wide-reaching implications in cell signaling and regulation [1,4].

In preosteoblastic MC3T3-E1 cells, TNF-α-induced pyroptosis during osteoblastic differentiation is mediated by ELP2. Forced ELP2 expression promotes cell pyroptosis, while ELP2 silencing ameliorates it and improves osteogenic differentiation [1]. ELP2 mutations in mice recapitulate features seen in patients with intellectual disability (ID) and autism spectrum disorder (ASD), including microcephaly, loss of white matter tract integrity, and an aberrant functional connectome. These mutations impact the activity of the elongator complex and its role in translation via tRNA modification, perturb protein homeostasis, and lead to impaired neurogenesis, myelin loss, and neurodegeneration [3]. In pancreatic cancer, an sQTL variant rs1785932-T allele promotes alternative splicing of ELP2 exon 6, resulting in a lower level of the ELP2 full-length isoform and a higher level of a truncated ELP2 isoform. The truncated isoform functions as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway [6].

In summary, Elp2 is essential for the proper assembly and function of the elongator complex, playing a role in multiple cellular processes. Model-based research, such as mouse models with Elp2 mutations, has revealed its significance in neurodevelopmental disorders like ID and ASD, as well as in osteogenic differentiation and pancreatic cancer. Understanding Elp2's functions provides insights into the underlying mechanisms of these diseases and may offer potential therapeutic targets [1,3,6].

References:

1. Xia, Changliang, Ou, Shuanji, Yang, Yang, Qi, Yong, Xu, Changpeng. 2023. ELP2-NLRP3-GSDMD/GSDME-mediated pyroptosis is induced by TNF-α in MC3T3-E1 cells during osteogenic differentiation. In Journal of cellular and molecular medicine, 27, 4093-4106. doi:10.1111/jcmm.17994. https://pubmed.ncbi.nlm.nih.gov/37830762/

2. Russo, Angelo, Forest, Cristina, Leone, Giulia Joy, Cordelli, Duccio Maria, Suppiej, Agnese. 2021. ELP2 compound heterozygous variants associated with cortico-cerebellar atrophy, nodular heterotopia and epilepsy: Phenotype expansion and review of the literature. In European journal of medical genetics, 64, 104361. doi:10.1016/j.ejmg.2021.104361. https://pubmed.ncbi.nlm.nih.gov/34653680/

3. Kojic, Marija, Gawda, Tomasz, Gaik, Monika, Glatt, Sebastian, Wainwright, Brandon J. 2021. Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype. In Nature communications, 12, 2678. doi:10.1038/s41467-021-22888-5. https://pubmed.ncbi.nlm.nih.gov/33976153/

4. Xu, Chang-Peng, Sun, Hong-Tao, Yang, Ya-Jun, Yang, Qing-Po, Qi, Yong. 2019. ELP2 negatively regulates osteoblastic differentiation impaired by tumor necrosis factor α in MC3T3-E1 cells through STAT3 activation. In Journal of cellular physiology, 234, 18075-18085. doi:10.1002/jcp.28440. https://pubmed.ncbi.nlm.nih.gov/30847950/

5. Dong, Chunming, Lin, Zhijie, Diao, Wentao, Shen, Yuequan, Long, Jiafu. 2015. The Elp2 subunit is essential for elongator complex assembly and functional regulation. In Structure (London, England : 1993), 23, 1078-86. doi:10.1016/j.str.2015.03.018. https://pubmed.ncbi.nlm.nih.gov/25960406/

6. Tian, Jianbo, Chen, Can, Rao, Meilin, Yang, Xiaojun, Miao, Xiaoping. . Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk. In Cancer research, 82, 2084-2096. doi:10.1158/0008-5472.CAN-21-4367. https://pubmed.ncbi.nlm.nih.gov/35363263/

7. Cohen, Julie S, Srivastava, Siddharth, Farwell, Kelly D, Chao, Elizabeth C, Fatemi, Ali. 2015. ELP2 is a novel gene implicated in neurodevelopmental disabilities. In American journal of medical genetics. Part A, 167, 1391-5. doi:10.1002/ajmg.a.36935. https://pubmed.ncbi.nlm.nih.gov/25847581/