EndoU, a ribonuclease, has diverse functions. In eukaryotes, it often requires divalent metal ions like calcium for activation, suggesting an evolutionary adaptation connecting its activity to cellular signaling [6]. It has been linked to various biological processes and diseases. For example, in coronaviruses, it targets viral RNA, cleaving at specific sequences (U↓A and C↓A) to evade dsRNA-activated host responses, thus playing a crucial role in viral replication and pathogenesis [1,3,7]. In bacteria, EndoU toxins show functional plasticity, with different clades having distinct substrate specificities [2].

In the context of mammalian cells, studies have shown its involvement in regulating translation. Overexpression of zebrafish or human ENDOU promotes translation of human CHOP mRNA by cleaving an inhibitory uORF element [4]. In cancer research, in oral squamous cell carcinoma, the circ_0049396/miR-663b/ENDOU axis has been identified, where circ_0049396 overexpression inhibits cell malignant behavior by regulating this axis [5]. In head and neck squamous cell carcinoma, ENDOU is identified as a biomarker, and its overexpression in vitro inhibits cell proliferation and migration [8]. Also, EndoU is a regulator of activation-induced cell death (AICD) during peripheral B cell selection, as its gene disruption prevents AICD and normalizes c-Myc expression [9].

In conclusion, EndoU is a multifunctional ribonuclease involved in diverse biological processes from viral replication to translation regulation and cancer progression. Studies using gene-related models (such as overexpression in cell lines) have revealed its roles in specific disease-related conditions like different types of carcinomas and in immune-related processes like B-cell selection. These findings contribute to understanding the underlying mechanisms of these biological processes and diseases, potentially paving the way for new therapeutic strategies.

References:

1. Ancar, Rachel, Li, Yize, Kindler, Eveline, Hesselberth, Jay R, Barton, David J. 2020. Physiologic RNA targets and refined sequence specificity of coronavirus EndoU. In RNA (New York, N.Y.), 26, 1976-1999. doi:10.1261/rna.076604.120. https://pubmed.ncbi.nlm.nih.gov/32989044/

2. Michalska, Karolina, Quan Nhan, Dinh, Willett, Julia L E, Joachimiak, Andrzej, Hayes, Christopher S. 2018. Functional plasticity of antibacterial EndoU toxins. In Molecular microbiology, 109, 509-527. doi:10.1111/mmi.14007. https://pubmed.ncbi.nlm.nih.gov/29923643/

3. Otter, Clayton J, Bracci, Nicole, Parenti, Nicholas A, Martinez-Sobrido, Luis, Weiss, Susan R. 2024. SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2320194121. doi:10.1073/pnas.2320194121. https://pubmed.ncbi.nlm.nih.gov/38568967/

4. Lee, Hung-Chieh, Fu, Chuan-Yang, Lin, Cheng-Yung, Sheu, Jin-Chuan, Tsai, Huai-Jen. 2021. Poly(U)-specific endoribonuclease ENDOU promotes translation of human CHOP mRNA by releasing uORF element-mediated inhibition. In The EMBO journal, 40, e104123. doi:10.15252/embj.2019104123. https://pubmed.ncbi.nlm.nih.gov/33511665/

5. Lou, Ying, Ren, Liuyang, Wang, Lu. 2022. Hsa_circ_0049396 inhibited oral squamous cell carcinoma progression by regulating the miR-663b/ENDOU axis. In Genomics, 115, 110553. doi:10.1016/j.ygeno.2022.110553. https://pubmed.ncbi.nlm.nih.gov/36581129/

6. Malard, Florian, Dias, Kristen, Baudy, Margaux, Karginov, Fedor V, Campagne, Sébastien. 2024. Molecular Basis for the Calcium-Dependent Activation of the Ribonuclease EndoU. In Research square, , . doi:10.21203/rs.3.rs-4654759/v1. https://pubmed.ncbi.nlm.nih.gov/39070628/

7. Zhou, Yiyang, Ahearn, Yani P, Lokugamage, Kumari G, Routh, Andrew L, Menachery, Vineet D. 2024. SARS-CoV-2 EndoU-ribonuclease regulates RNA recombination and impacts viral fitness. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.11.11.622995. https://pubmed.ncbi.nlm.nih.gov/39605585/

8. Xu, Chengzhi, Zhang, Yunbin, Shen, Yupeng, Zhang, Ming, Zhou, Liang. 2021. Integrated Analysis Reveals ENDOU as a Biomarker in Head and Neck Squamous Cell Carcinoma Progression. In Frontiers in oncology, 10, 522332. doi:10.3389/fonc.2020.522332. https://pubmed.ncbi.nlm.nih.gov/33614471/

9. Poe, Jonathan C, Kountikov, Evgueni I, Lykken, Jacquelyn M, Marchuk, Douglas A, Tedder, Thomas F. 2013. EndoU is a novel regulator of AICD during peripheral B cell selection. In The Journal of experimental medicine, 211, 57-69. doi:10.1084/jem.20130648. https://pubmed.ncbi.nlm.nih.gov/24344237/