Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seems to employ two routes of entrance to the host cell; via membrane fusion (with the cells expressing both angiotensin converting enzyme 2 (ACE2) and transmembrane peptidase/serine subfamily member 2/4 (TMPRSS2/4)) or via receptor-mediated endocytosis (to the target cells expressing only ACE2). The second mode is associated with cysteine cathepsins (probably cathepsin L) involvement in the virus spike protein (S protein) proteolytic activation. Also furin might activate the virus S protein enabling it to enter cells. Gastrointestinal tract (GIT) involvement in SARS-CoV-2 infection is evident in a subset of coronavirus disease 2019 (COVID-19) patients exhibiting GIT symptoms, such as diarrhea, and presenting viral-shedding in feces. Considering the abundance and co-localization of ACE2 and TMPRSS2 in the lower GIT (especially brush-border enterocytes), these two receptors seem to be mainly involved in SARS-CoV-2 invasion of the digestive tract. Additionally, in vitro studies have demonstrated the virions capability of infection and replication in the human epithelial cells lining GIT. However, also furin and cysteine cathepsins (cathepsin L) might participate in the activation of SARS-CoV-2 spike protein contributing to the virus invasiveness within GIT. Moreover, cathepsin L (due to its involvement in extracellular matrix components degradation and remodeling, the processes enhanced during SARS-CoV-2-induced inflammation) might be responsible for the dysregulation of absorption/ digestion functions of GIT, thus adding to the observed in some COVID-19 patients symptoms such as diarrhea.

Impact of various buffers and weak bases on lysosomal and intracellular pH: Implications for infectivity of SARS‐CoV‐2

“…18 These viruses can directly fuse at the cell surface if the spike protein is cleaved by a surface protease like TMPRSS2, 19 or utilizes an endosome-lysosomal route for fusion, where the Spike protein is primed by cysteine protease cathepsins. 20 Regarding the role of the acidic endosome-lysosomal pathway in infection, cathepsins function optimally in a low pH environment. 21 The dynamin and clathrinindependent CLIC/GEEC (CG) endocytic pathway, 22 is also pH-dependent.…”

Persistent Immune and Clotting Dysfunction Detected in Saliva and Blood Plasma after COVID-19

“…If not limited to the proteins upregulated by 2 fold or higher, convalescent saliva showed increase in numerous proteins associated with neutrophil functions or migration, such as Annexin 1 40,41 , antileukoproteinase 42 , and Matrix metalloproteinase-9 43,44 ( Table 1A ). At the same time, the convalescent saliva showed significant increase in transmembrane protease serine 11D, which is known to activate the SARS-CoV-2 spike protein and facilitate the viral-cell fusion process 45,46 . It warrants that neutrophil-driven innate immune response at oral mucosa initiates a dysbiotic cycle, tissue damage that ultimately leads to prolonged infection-inflammation sequelae.…”

“…Interestingly, salivary proteome appears to maintain activated inflammatory status longer than plasma, as significantly increased neutrophil activation markers, myeloperoxidase (MPO), annexin 1-2, alpha-actinin-1, and nuclear transport factor 2 are involved in the migration of neutrophils ( 30–32 ). The convalescent saliva fluid also showed a significant increase in transmembrane protease serine 11D, which is known to activate the SARS-CoV-2 spike protein and facilitate the viral-cell fusion process ( 33, 34 ), and serpin B13, known for regulating neutrophil serine proteases and inflammatory caspases ( 35 ) ( Table 1B ). Other interesting proteins found in our study are the inhibitors of cathepsin, which have been involved in viral cell entry and replication ( 36 ).…”

Recent applications of computational methods to allosteric drug discovery

“…Cathepsins are members of the papain superfamily of cysteine proteases. They are generally localized within the lysosomes where they have key roles in functions such as protein degradation, autophagy, cell death and more ( Novinec et al, 2014a ; Olson and Joyce, 2015 ; Berdowska et al, 2021 ; Gaire et al, 2021 ; Yoo et al, 2022 ). In most situations, the proteolytic activity of cathepsins is restricted to the acidic environment within the lysosomes ( Verma et al, 2016 ).…”

“…Further, non-proteolytic collagenase activity has been proposed for the extra-lysosomal cathepsins in the extracellular matrix ( Novinec and Lenarčič, 2013 ; Novinec et al, 2014b ). Very recently, cathepsin L was reported to be involved in the activation of SARS-CoV-2 spike protein within the gastrointestinal tract ( Berdowska et al, 2021 ).…”