{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cathepsin L (CTSL) is a versatile lysosomal cysteine protease that plays multiple roles in both physiological and pathological processes. Several studies have demonstrated that CTSL facilitates the proteolytic cleavage of viral glycoproteins to enable virus entry and disassembly. For example, it provides accessory proteolysis for Ebola virus glycoprotein activation, is a primary mediator of reovirus disassembly, and is required for the endosomal entry of several coronaviruses—including SARS‐, MERS‐, and SARS‑CoV‑2—by cleaving their spike proteins; indeed, inhibition of CTSL can block viral infection (see, for example,"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": ").\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in viral pathogenesis, CTSL contributes to proinflammatory signaling. It is involved in proteolytic processing events that activate the NLRP3 inflammasome in response to endogenous danger signals such as cholesterol crystals, and it participates in the proteolytic cleavage of Toll-like receptor 9 (TLR9), thereby facilitating innate immune responses associated with atherosclerosis and inflammatory bowel disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n CTSL also exerts critical functions in intracellular protein processing that impact cellular homeostasis and differentiation. It cleaves cytosolic proteins such as Tau, generating amyloidogenic fragments implicated in neurodegeneration, and it processes nuclear substrates including the transcription factor CDP/Cux and the N-terminal tail of histone H3—actions that affect cell cycle progression and epigenetic remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the extracellular compartment, CTSL contributes to matrix remodeling by degrading extracellular matrix proteins. This proteolysis is essential for endothelial progenitor cell invasion and neovascularization, and its overexpression in vascular lesions is associated with pathological remodeling seen in aneurysms and atherosclerosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, CTSL is involved in the generation of bioactive peptides; it processes proenkephalin in secretory vesicles to yield enkephalin, an endogenous neuropeptide, and it participates in proteolytic cascades that regulate skeletal muscle mass as well as podocyte actin dynamics—processes whose dysregulation can lead to muscle atrophy and proteinuric kidney injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the pleiotropic roles of cathepsin L in viral entry, inflammatory signaling, intracellular protein and chromatin processing, extracellular matrix remodeling, and tissue homeostasis. The diverse functions of CTSL not only highlight its importance in fundamental cellular processes but also nominate it as a promising therapeutic target across a broad spectrum of diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kartik Chandran, Nancy J Sullivan, Ute Felbor, et al. 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