{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNSP4, also known as PRSS57, is a serine protease prominently expressed in human neutrophils. It is synthesized during early granulocytic differentiation—with mRNA levels peaking in myeloblasts and promyelocytes similarly to markers such as myeloperoxidase—and is stored as an activated enzyme in azurophil granules. In neutrophils, this enzyme is fully processed and rapidly deployed upon activation, and its maturation critically depends on cathepsin C, as evidenced by its complete absence in patients lacking this activator."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDespite being a member of the trypsin-fold protease family, NSP4 (PRSS57) exhibits a paradoxical combination of structural features. Although it possesses elastase-like residues in its active site, NSP4 displays a unique trypsin-like substrate specificity by cleaving after arginine residues. Structural analyses revealed that its S1 pocket is fully occluded, and the substrate’s P1-arginine is oriented in a noncanonical “up” conformation stabilized by a solvent-exposed hydrogen bond network. This unusual architecture enables NSP4 to process not only standard arginine substrates but also post-translationally modified arginine residues, such as methylarginine and citrulline."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a distinct context, another protein designated NSP4 refers to a non-structural protein of SARS-CoV-2 that plays a key role in viral replication and immune modulation. A specific T492I mutation in viral NSP4 enhances the replication capacity and infectiveness of the virus by increasing the cleavage efficiency of the viral main protease NSP5, thereby boosting the production of nearly all non-structural proteins. This mutation also contributes to the virus’s ability to evade host immune responses by suppressing chemokine production in monocytic macrophages."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Natascha C Perera, Karl-Heinz Wiesmüller, Maria Torp Larsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NSP4 is stored in azurophil granules and released by activated neutrophils as active endoprotease with restricted specificity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1301293"}], "href": "https://doi.org/10.4049/jimmunol.1301293"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23904161"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23904161"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "S Jack Lin, Ken C Dong, Charles Eigenbrot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures of neutrophil serine protease 4 reveal an unusual mechanism of substrate recognition by a trypsin-fold protease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2014.07.008"}], "href": "https://doi.org/10.1016/j.str.2014.07.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25156428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25156428"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaoyuan Lin, Zhou Sha, Jakob Trimpert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The NSP4 T492I mutation increases SARS-CoV-2 infectivity by altering non-structural protein cleavage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Host Microbe (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chom.2023.06.002"}], "href": "https://doi.org/10.1016/j.chom.2023.06.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37402373"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37402373"}]}]}]}