The transmembrane protease, serine 2 (TMPRSS2), is an enzyme anchored to the surface of human cells. This protein belongs to the family of serine proteases, which function by cutting specific peptide bonds in other proteins. While TMPRSS2 performs routine biological tasks, it is widely recognized for its ability to be exploited by various pathogens. It acts as a co-factor, modifying viral surface proteins and enabling the pathogen to breach the host cell membrane to initiate infection. Understanding this dual nature is crucial for developing strategies to combat infectious diseases and certain cancers.
TMPRSS2’s Normal Physiological Function
TMPRSS2 is a type II transmembrane serine protease, embedded within the cell membrane with its active enzymatic domain facing the outside environment. Its primary non-pathogenic role involves participating in proteolytic cascades necessary for routine cellular maintenance. The enzyme is initially synthesized as an inactive precursor (zymogen) and must undergo autocleavage to become fully active.
A defined normal role for TMPRSS2 is the activation of the epithelial sodium channel (ENaC), particularly in the respiratory tract. ENaC regulates the transport of sodium ions across epithelial cell layers, influencing fluid balance in the airways. By cleaving ENaC at multiple sites, TMPRSS2 helps maintain the proper hydration of the lung surface, which is necessary for mucociliary clearance.
The enzyme is also highly expressed in the prostate, where its function is regulated by androgen hormones. In this tissue, TMPRSS2 contributes to the local proteolytic environment necessary for normal prostate function. It also participates in activating other enzymes, such as the precursor of hepatocyte growth factor, which plays a role in tissue repair and cell movement. These localized actions highlight its importance in tissue-specific homeostasis.
How TMPRSS2 Activates Viral Entry
The mechanism by which TMPRSS2 facilitates viral infection is known as proteolytic priming, which is required for the virus to fuse its membrane with the host cell membrane. Many respiratory viruses, including coronaviruses and influenza viruses, possess large surface proteins that must be structurally altered to become infectious. The enzyme modifies the viral surface protein by cutting it at a specific location, exposing a section that mediates membrane fusion.
Coronaviruses, such as the one responsible for COVID-19, use the Angiotensin-Converting Enzyme 2 (ACE2) receptor to anchor to the host cell surface. Once bound, the virus requires TMPRSS2, often located adjacent to ACE2, to cleave its Spike (S) protein. This cleavage occurs at two main sites: the S1/S2 boundary and the S2′ site.
The initial cut at the S1/S2 site primes the Spike protein. The subsequent cleavage at the S2′ site releases the fusion peptide, which inserts itself into the host cell membrane. This initiates a conformational change in the Spike protein structure that pulls the viral envelope and the host cell membrane together until they merge, allowing the viral genetic material to enter the cytoplasm.
This mechanism allows the virus to enter the cell directly at the surface, bypassing the endosomal pathway. TMPRSS2 is also the major activating protease for the Hemagglutinin (HA) protein of many influenza A and B viruses in the human airway. Cleavage of the HA protein is required for the virus to replicate and spread effectively within the respiratory tract.
Tissue Expression and Disease Association
The distribution of TMPRSS2 throughout the body dictates which tissues are most susceptible to viral infection and provides insight into its disease associations. The gene is highly expressed in the epithelial cells lining the respiratory tract, including the nasal passages and the lungs, which explains its involvement in respiratory viral infections. High levels of the enzyme are also found in the epithelial cells of the gastrointestinal tract and the kidney.
Beyond its role in infectious disease, TMPRSS2 is notably implicated in prostate cancer, a connection that was recognized long before its link to viral entry. The gene is located on chromosome 21 and is under the control of androgen hormones, which primarily drive its expression in the prostate. In a significant number of prostate cancer cases, the gene undergoes a chromosomal rearrangement, fusing with an oncogenic transcription factor gene, most commonly ERG.
This fusion, known as the TMPRSS2-ERG fusion, places the ERG gene under the regulatory control of the TMPRSS2 promoter. Because the TMPRSS2 promoter is strongly activated by androgens, this rearrangement leads to the overexpression of the ERG protein, which drives the cancerous transformation of the cell. This genetic alteration is a common molecular signature in prostate tumors and highlights how the enzyme’s normal regulation can be hijacked to promote malignant growth.
Targeting TMPRSS2 for Therapeutic Intervention
The central role of TMPRSS2 in both viral entry and cancer progression makes it an appealing target for therapeutic development. Inhibiting the enzyme’s proteolytic activity offers a two-pronged strategy: blocking the first step of viral infection and potentially hindering cancer progression. The goal of such drugs is to neutralize the enzyme’s cutting ability without causing unacceptable side effects.
One prominent example of an inhibitor is camostat mesylate, a drug that has been used clinically in Japan for conditions like chronic pancreatitis and reflux esophagitis. Camostat and its more potent derivative, nafamostat mesylate, function as serine protease inhibitors, directly binding to and inactivating the TMPRSS2 enzyme. These compounds have been investigated in clinical trials for their ability to prevent the enzyme from priming viral spike proteins, thereby reducing viral entry into host cells.
Developing highly specific inhibitors for TMPRSS2 presents a challenge because the body contains many different serine proteases that perform important functions. A lack of specificity could lead to unwanted inhibition of other necessary enzymes, potentially disrupting coagulation or other proteolytic cascades. Despite these hurdles, the enzyme’s location on the cell surface and its involvement in the entry step of multiple respiratory viruses continue to drive research into novel, highly selective inhibitors that could serve as broad-spectrum antiviral agents.