MTR4, also known as MTREX, is a Ski2-like RNA helicase. It is a central activator of the RNA exosome, playing a crucial role in RNA surveillance and degradation pathways. These pathways are essential for maintaining proper cellular function by ensuring the quality control of RNA molecules, which impacts various biological processes [1].

In HIV-1 latency, MTR4, along with MATR3, is involved in regulating unspliced HIV-1 RNA. MTR4 functions to degrade the RNA, while Rev controls this regulatory switch, highlighting its role in post-transcriptional regulation relevant to HIV-1 reactivation and curative interventions [2]. MTR4, along with other factors like RRP6, ZCCHC8, and ZFC3H1, associates with the HIV-1 TAR region, repressing transcriptional output, which identifies it as part of a network of transcriptional repressors for HIV-1 [3]. The hnRNPH1-MTR4 complex regulates the stability of NEAT1v2, an lncRNA, which in turn is critical for IL8 expression, showing its role in innate immune response-related gene regulation [4]. PICT1, an MTR4 adaptor, is involved in two distinct pre-rRNA processing steps during 60S ribosome generation in human cells, suggesting MTR4's importance in ribosome biogenesis [5]. In nasopharyngeal carcinoma, MTR4 drives tumorigenesis by regulating key cell cycle genes [6]. In schizophrenia patients, the expression levels of MTR4 (MTREX) in olfactory neuroepithelial cells correlate with cognitive markers and clinical signs, indicating its potential role in understanding the influence of cannabis use on schizophrenia [7]. ARS2's interaction with MTR4, a part of the PAXT connection, is crucial for ARS2-mediated RNA decay, mapping the domains of ARS2 involved in recruiting the RNA decay machinery [8].

In summary, MTR4 is a vital RNA helicase in RNA surveillance and degradation. Its functions have been revealed through various disease-related studies such as in HIV-1 latency, cancer, and schizophrenia. These model-based research findings help understand the role of MTR4 in disease-associated biological processes, potentially paving the way for therapeutic interventions.

References:

1. Olsen, Keith J, Johnson, Sean J. 2021. Mtr4 RNA helicase structures and interactions. In Biological chemistry, 402, 605-616. doi:10.1515/hsz-2020-0329. https://pubmed.ncbi.nlm.nih.gov/33857361/

2. Dorman, Agnieszka, Bendoumou, Maryam, Valaitienė, Aurelija, Van Lint, Carine, Kula-Pacurar, Anna. 2025. Nuclear retention of unspliced HIV-1 RNA as a reversible post-transcriptional block in latency. In Nature communications, 16, 2078. doi:10.1038/s41467-025-57290-y. https://pubmed.ncbi.nlm.nih.gov/40021667/

3. Contreras, Xavier, Salifou, Kader, Sanchez, Gabriel, Rouquier, Sylvie, Kiernan, Rosemary. 2018. Nuclear RNA surveillance complexes silence HIV-1 transcription. In PLoS pathogens, 14, e1006950. doi:10.1371/journal.ppat.1006950. https://pubmed.ncbi.nlm.nih.gov/29554134/

4. Tanu, Tanzina, Taniue, Kenzui, Imamura, Katsutoshi, Jensen, Torben Heick, Akimitsu, Nobuyoshi. 2021. hnRNPH1-MTR4 complex-mediated regulation of NEAT1v2 stability is critical for IL8 expression. In RNA biology, 18, 537-547. doi:10.1080/15476286.2021.1971439. https://pubmed.ncbi.nlm.nih.gov/34470577/

5. Miyao, Sotaro, Saito, Kanako, Oshima, Renta, Kawahara, Kohichi, Nagahama, Masami. 2022. MTR4 adaptor PICT1 functions in two distinct steps during pre-rRNA processing. In Biochemical and biophysical research communications, 637, 203-209. doi:10.1016/j.bbrc.2022.11.018. https://pubmed.ncbi.nlm.nih.gov/36403484/

6. Yu, Lili, Jiang, Lei, Wu, Meng, Kim, Jinchul, Xu, Yang. . RNA helicase MTR4 drives tumorigenesis of nasopharyngeal carcinoma by regulating the expression of key cell cycle genes. In Protein & cell, 14, 149-152. doi:10.1093/procel/pwac003. https://pubmed.ncbi.nlm.nih.gov/36929008/

7. Barrera-Conde, Marta, Ausin, Karina, Lachén-Montes, Mercedes, Santamaría, Enrique, Robledo, Patricia. 2021. Cannabis Use Induces Distinctive Proteomic Alterations in Olfactory Neuroepithelial Cells of Schizophrenia Patients. In Journal of personalized medicine, 11, . doi:10.3390/jpm11030160. https://pubmed.ncbi.nlm.nih.gov/33668817/

8. Melko, Mireille, Winczura, Kinga, Rouvière, Jérôme Olivier, Andersen, Pia K, Heick Jensen, Torben. . Mapping domains of ARS2 critical for its RNA decay capacity. In Nucleic acids research, 48, 6943-6953. doi:10.1093/nar/gkaa445. https://pubmed.ncbi.nlm.nih.gov/32463452/