TMPRSS2

TMPRSS2 stands for transmembrane protease, serine 2, a human protein encoded by the TMPRSS2 gene. It is a member of the type II transmembrane serine protease (TTSP) family and features a single transmembrane domain with an extracellular serine protease catalytic domain. The gene is located on chromosome 21q22.3 and the protein is expressed in several tissues, with notable levels in the prostate as well as in the respiratory and gastrointestinal epithelium.

In the prostate, TMPRSS2 expression is driven by androgens via the androgen receptor, contributing to its pronounced activity in androgen-responsive tissues. The physiological substrates of TMPRSS2 are not fully mapped, but the protease cleaves and activates multiple protein substrates, and it participates in processing viral and host proteins that influence cell signaling and proteolysis.

A key area of interest is TMPRSS2’s role in viral entry. The extracellular protease can prime the spike proteins of certain coronaviruses, including SARS-CoV-2, facilitating entry of the virus into host cells. Because of this role, TMPRSS2 is a target for therapeutic strategies aimed at blocking viral entry. Pharmacologic inhibitors such as camostat mesylate and nafamostat have been studied as potential treatments.

In cancer, TMPRSS2 is best known for forming gene fusions with ETS transcription factors, most notably TMPRSS2-ERG, in a substantial subset of prostate cancers. This fusion places ERG under the control of the androgen-responsive TMPRSS2 promoter, promoting oncogenic ERG expression.

Research in model systems suggests that TMPRSS2 is not essential for normal viability, and targeted inhibition may reduce susceptibility to certain viral infections while limiting adverse effects. Ongoing work explores broader physiological roles and the development of selective inhibitors for clinical use.