Mutations of the TMPRSS2 gene are often involved in prostate cancer. Several viruses, including SARS-CoV-2, use the protease activity of the TMPRSS2 protein in the process of entering cells.[8]
As a type II transmembrane protease, TMPRSS2 consists of an intracellular N-terminal domain, a transmembrane domain, a stem region that extends extracellularly and a C-terminal domain that catalyzes its serine protease (SP) activity.[12] This serine protease activity is orchestrated by a catalytic triad containing the residues His296, Asp345, and Ser441.[12][10] This noted catalytic triad is typically responsible for the cleaving of basic amino acid residues (lysine or arginine residues)— consistent with what is observed in the S1/S2 cleavage site found in SARS-CoV-2.[12] A notable domain in the stem region that has been examined through mutational analysis is the low density lipoprotein receptor class A domain (LDLRA).[12] Experimental evidence suggests that this domain likely participates in enzymatic activity of the protein and has been examined alongside another motif in the stem region: the scavenger receptor cysteine-rich domain (SRCR).[12] This domain may be implicated in the binding of extracellular molecules and other nearby cells.[13][14] Interestingly, SRCR may have a role in overall proteolytic activity of the protein, which could lead to implications on the overall virulence of SARS-CoV-2.[15][12][16]
TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression of ETS transcription factors, such as ERG and ETV1, through gene fusion. TMPRSS2-ERG fusion gene is the most frequent, present in 40% - 80% of prostate cancers in humans. ERG overexpression contributes to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling.[17]
Coronaviruses
Some coronaviruses, e.g. SARS-CoV-1, MERS-CoV, and SARS-CoV-2 (although less well by the omicron variant[18]), are activated by TMPRSS2 and can thus be inhibited by TMPRSS2 inhibitors.[19][20]SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.[21]
Cleavage of the SARS-CoV-2S2spike protein required for viral entry into cells can be accomplished by proteases TMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes.[22]Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.[22]
The enzyme Adam17 has similar ACE2 cleavage activity as TMPRSS2, but by forming soluble ACE2, Adam17 may actually have the protective effect of blocking circulating SARS‑CoV‑2 virus particles.[23] By not releasing soluble ACE2, TMPRSS2 cleavage is more harmful.[23]
A TMPRSS2 inhibitor such as camostat approved for clinical use blocked entry and might constitute a treatment option.[20][22] Another experimental candidate as a TMPRSS2 inhibitor for potential use against both influenza and coronavirus infections in general, including those prior to the advent of COVID-19, is the over-the-counter (in most countries) mucolytic cough medicine bromhexine,[24] which is also being investigated as a possible treatment for COVID-19 itself as well.[25] The fact that TMPRSS2 has no known irreplaceable function makes it a promising target for preventing SARS-CoV-2 virus transmission.[9]
The fact that severe illness and death from Sars-Cov-2 is more common in males than females, and that TMPRSS2 is expressed several times more highly in prostateepithelium than any tissue, suggests a role for TMPRSS2 in the gender difference.[26][27]Prostate cancer patients receiving androgen deprivation therapy have a lower risk of SARS-CoV-2 infection than those not receiving that therapy.[26][27]
Inhibitors
Camostat is an inhibitor of the serine protease activity of TMPRSS2. It is used to treat pancreatitis and reflux esophagitis.[28] It was found not to be effective against COVID-19.[29] A novel inhibitor of TMPRSS2 (N-0385) has been found to be effective against SARS-CoV-2 infection in cell and animal models.[30]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3". Genomics. 44 (3): 309–320. doi:10.1006/geno.1997.4845. PMID9325052.
^Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (September 1997). "Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3". Genomics. 44 (3): 309–320. doi:10.1006/geno.1997.4845. PMID9325052.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK (June 2001). "Mutation analyses of 268 candidate genes in human tumor cell lines". Genomics. 74 (3): 352–364. doi:10.1006/geno.2001.6551. PMID11414763.
Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R, Panagopoulos I (July 2006). "Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer". Genes, Chromosomes & Cancer. 45 (7): 717–719. doi:10.1002/gcc.20329. PMID16575875. S2CID86518137.