Tmprss2-KO Mouse

Tmprss2, short for transmembrane serine protease 2, is a type II transmembrane protease encoded by the TMPRSS2 gene. It has two autocatalytically activated isoforms from its inactive zymogen form. Functionally, it is involved in priming viral spike proteins, facilitating viral entry and thus viral infectivity. It also has been associated with the renin-angiotensin system and may play a role in various biological processes in epithelial cells of the respiratory, gastrointestinal tract, and prostate [3,4,5,6,7].

Regarding its role in diseases, Tmprss2 has been extensively studied in relation to viral infections and cancer. In the context of viral infections, it serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses like human coronavirus HKU1 [3,4,6]. HKU1 uses both sialoglycan and Tmprss2 for cellular entry, where sialoglycan primes the spike protein for Tmprss2 binding, and Tmprss2 undergoes autocleavage to enhance its affinity for the HKU1 spike [2]. In cancer, a fusion gene between TMPRSS2 and ERG (an oncogenic transcription factor) is a common chromosomal aberration in prostate cancer, driving carcinogenesis [7]. Depletion of Tmprss2 in lung cancer cells suppressed anchorage-independent growth and xenograft tumor growth in mice, indicating its role in lung cancer progression as PM2.5 activates AhR to upregulate Tmprss2 and IL18 expression [1].

In conclusion, Tmprss2 is crucial in both viral infectivity and cancer-related processes. Its role in facilitating viral entry for various coronaviruses and its association with cancer development, as revealed through in vivo studies (although no KO/CKO mouse models were specifically detailed in the provided references), highlight its potential as a therapeutic target for treating viral infections and certain cancers.

References:

1. Wang, Tong-Hong, Huang, Kuo-Yen, Chen, Chin-Chuan, Yang, Pan-Chyr, Chen, Chi-Yuan. 2023. PM2.5 promotes lung cancer progression through activation of the AhR-TMPRSS2-IL18 pathway. In EMBO molecular medicine, 15, e17014. doi:10.15252/emmm.202217014. https://pubmed.ncbi.nlm.nih.gov/36975376/

2. Pan, Zhengyang, Li, Daoqun, Zhang, Leiliang. 2024. TMPRSS2 in microbial interactions: Insights from HKU1 and TcsH. In PLoS pathogens, 20, e1012677. doi:10.1371/journal.ppat.1012677. https://pubmed.ncbi.nlm.nih.gov/39565778/

3. Wettstein, Lukas, Kirchhoff, Frank, Münch, Jan. 2022. The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment. In International journal of molecular sciences, 23, . doi:10.3390/ijms23031351. https://pubmed.ncbi.nlm.nih.gov/35163273/

4. Dong, Mengzhen, Zhang, Jie, Ma, Xuefeng, Xin, Yongning, Zhuang, Likun. 2020. ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 131, 110678. doi:10.1016/j.biopha.2020.110678. https://pubmed.ncbi.nlm.nih.gov/32861070/

5. Zipeto, Donato, Palmeira, Julys da Fonseca, Argañaraz, Gustavo A, Argañaraz, Enrique R. 2020. ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19. In Frontiers in immunology, 11, 576745. doi:10.3389/fimmu.2020.576745. https://pubmed.ncbi.nlm.nih.gov/33117379/

6. Abbasi, Asim Z, Kiyani, Dania A, Hamid, Syeda M, Fahim, Ammad, Jalal, Nasir. 2021. Spiking dependence of SARS-CoV-2 pathogenicity on TMPRSS2. In Journal of medical virology, 93, 4205-4218. doi:10.1002/jmv.26911. https://pubmed.ncbi.nlm.nih.gov/33638460/

7. Thunders, Michelle, Delahunt, Brett. 2020. Gene of the month: TMPRSS2 (transmembrane serine protease 2). In Journal of clinical pathology, 73, 773-776. doi:10.1136/jclinpath-2020-206987. https://pubmed.ncbi.nlm.nih.gov/32873700/