The Key Role of Lysosomal Protease Cathepsins in Viral Infections

Abstract

Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein processing and trafficking through the plasma and nuclear membrane and between intracellular organelles. Ubiquitously expressed in the body, cathepsins play regulatory roles in a wide range of physiological processes including coagulation, hormone secretion, immune responses, and others. A dysregulation of cathepsin expression and/or activity has been associated with many human diseases, including cancer, diabetes, obesity, cardiovascular and inflammatory diseases, kidney dysfunctions, and neurodegenerative disorders, as well as infectious diseases. In viral infections, cathepsins may promote (1) activation of the viral attachment glycoproteins and entry of the virus into target cells; (2) antigen processing and presentation, enabling the virus to replicate in infected cells; (3) up-regulation and processing of heparanase that facilitates the release of viral progeny and the spread of infection; and (4) activation of cell death that may either favor viral clearance or assist viral propagation. In this review, we report the most relevant findings on the molecular mechanisms underlying cathepsin involvement in viral infection physiopathology, and we discuss the potential of cathepsin inhibitors for therapeutical applications in viral infectious diseases.

Cathepsins and SARS‐CoV‐2 infection: From pathogenic factors to potential therapeutic targets

“…As mentioned above, it is clear that cathepsins play an essential role in the pathology and pathogenesis of COVID‐19. Cathepsins perform the function in the cleavage of the spike protein of SARS‐CoV‐2 which is crucial for the SARS‐CoV‐2 infection and take part in the immune response caused by SARS‐CoV‐2 (Anes et al, 2022; Scarcella et al, 2022). Thus, cathepsins are attractive drug targets for treating COVID‐19.…”

“…If TMPRSS2 expression on the cell surface is too low, or the ACE2‐bound SARS‐CoV‐2 is internalized by clathrin‐mediated endocytosis, then cathepsins perform their function (Jackson et al, 2022). Among all cathepsins, there is solid evidence that CatL and CatB take part in cleavage of the S protein in SARS‐CoV‐2, whereas CatK, CatS and CatV are suspective of involving in this process (Ashhurst et al, 2022; Bollavaram et al, 2021; Scarcella et al, 2022; Shang, Wan, et al, 2020; Zhao et al, 2021) (Gomes et al, 2020). Jaimes' study showed that S1/S2 spike protein sites of SARS‐CoV‐2 can be cleaved by CatB and CatL (Jaimes et al, 2020).…”

“…Cathepsins (especially CatB and CatL) have been demonstrated to be involved in COVID‐19 pathogenesis and their deletion can decrease disease progression significantly. Therefore, inhibitors targeting CatB and CatL could alleviate COVID‐19 pathogenesis (Muralidar et al, 2021; Pislar et al, 2020; Scarcella et al, 2022). Inhibitors targeting cathepsins in COVID‐19 therapy are summarized in Tables 1 and 2.…”

Cathepsin-Targeting SARS-CoV-2 Inhibitors: Design, Synthesis, and Biological Activity

“…It is followed by S protein priming within the S1 domain, a process that occurs in the acidic endosomal–lysosomal compartment, where TMPRSS2 is not catalytically competent. Here, the cleavage of the SARS-CoV-2 S protein is catalyzed by human lysosomal cathepsins (Cats). − In particular, CatL has a crucial role in SARS-CoV-2 infection. It effectively cleaves the SARS-CoV-2 S protein, enhancing virus entry …”

Roles of host proteases in the entry of SARS-CoV-2

“…, suggesting there are variations on the virus entry among SARS-CoV-2 variants. Cathepsins are mainly localized in the endolysosomes and perform a variety of functions such as processing proproteins, hormones and antigens(Yadati et al 2020;Scarcella et al 2022). The key cathepsin protease utilized by coronaviruses for cell entry is cathepsin L, a cysteine protease which preferentially cleaves peptide bonds with nonpolar, aromatic residues(Biniossek et al 2011).…”