Cathepsin L1 Explained

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene.^{[1] [2] [3]} The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.^{[4] [5] [6] [7]}

Function

Cathepsin L1 is a member of the Peptidase C1 (cathepsin) MEROPS family, which plays an important role in diverse processes including normal lysosome mediated protein turnover, antigen and proprotein processing, and apoptosis.^[8] Its substrates include collagen and elastin, as well as alpha-1 protease inhibitor, a major controlling element of neutrophil elastase activity. The encoded protein has been implicated in several pathologic processes, including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria. This protein, which is a member of the peptidase C1 family, is a dimer composed of disulfide-linked heavy and light chains, both produced from a single protein precursor. At least two transcript variants encoding the same protein have been found for this gene.^[3]

Viral entry

Cleavage of the SARS-CoV-2 S2 spike protein required for viral entry into cells can be accomplished by proteases TMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes.^[9] Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.

Inflammation

Although Cathepsin L is usually characterized as a lysosomal protease, it can be secreted, resulting in pathological inflammation.^[10] Cathepsin L and other cysteine cathepsins tend to be secreted by macrophages and other tissue-invading immune cells when causing pathological inflammation.^[11]

Interactions

CTSL1 has been shown to interact with Cystatin A.^{[12] [13]}

Distribution

Cathepsin L has been reported in many organisms including fish,^[14] birds, mammals, and sponges.^[15]

See also

• Cathepsin L2 (also known as cathepsin V)

Further reading

• Smith CG, Smith MT, Besch NF . Effect of delta 9-tetrahydrocannabinol (THC) on female reproductive function. . Advances in the Biosciences . 22-23 . 449–67 . 1980 . 116880 . 10.1016/b978-0-08-023759-6.50040-8. 9780080237596 . etal.
• Goretzki L, Schmitt M, Mann K . Effective activation of the proenzyme form of the urokinase-type plasminogen activator (pro-uPA) by the cysteine protease cathepsin L. . FEBS Lett. . 297 . 1–2 . 112–8 . 1992 . 1551416 . 10.1016/0014-5793(92)80339-I . 45421148 . etal. free . 1992FEBSL.297..112G .
• Dunn AD, Crutchfield HE, Dunn JT . Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L. . J. Biol. Chem. . 266 . 30 . 20198–204 . 1991 . 10.1016/S0021-9258(18)54909-7 . 1939080 . free .
• Stearns NA, Dong JM, Pan JX . Comparison of cathepsin L synthesized by normal and transformed cells at the gene, message, protein, and oligosaccharide levels. . Arch. Biochem. Biophys. . 283 . 2 . 447–57 . 1991 . 2275556 . 10.1016/0003-9861(90)90666-M . etal.
• Ritonja A, Popović T, Kotnik M . Amino acid sequences of the human kidney cathepsins H and L. . FEBS Lett. . 228 . 2 . 341–5 . 1988 . 3342889 . 10.1016/0014-5793(88)80028-0 . 45768546 . etal. free . 1988FEBSL.228..341R .
• Gal S, Gottesman MM . Michael M. Gottesman . Isolation and sequence of a cDNA for human pro-(cathepsin L). . Biochem. J. . 253 . 1 . 303–6 . 1988 . 3421948 . 1149292 . 10.1042/bj2530303.
• Johnson DA, Barrett AJ, Mason RW . Cathepsin L inactivates alpha 1-proteinase inhibitor by cleavage in the reactive site region. . J. Biol. Chem. . 261 . 31 . 14748–51 . 1986 . 10.1016/S0021-9258(18)66935-2 . 3490478 . free .
• Mason RW, Walker JE, Northrop FD . The N-terminal amino acid sequences of the heavy and light chains of human cathepsin L. Relationship to a cDNA clone for a major cysteine proteinase from a mouse macrophage cell line. . Biochem. J. . 240 . 2 . 373–7 . 1987 . 3545185 . 1147428 . 10.1042/bj2400373.
• Joseph L, Lapid S, Sukhatme V . The major ras induced protein in NIH3T3 cells is cathepsin L. . Nucleic Acids Res. . 15 . 7 . 3186 . 1987 . 3550705 . 340927 . 10.1093/nar/15.7.3186 .
• Kärgel HJ, Dettmer R, Etzold G . Action of rat liver cathepsin L on glucagon. . Acta Biol. Med. Ger. . 40 . 9 . 1139–43 . 1982 . 7340337 . etal.
• Bevec T, Stoka V, Pungercic G . Major histocompatibility complex class II-associated p41 invariant chain fragment is a strong inhibitor of lysosomal cathepsin L. . J. Exp. Med. . 183 . 4 . 1331–8 . 1996 . 8666891 . 2192513 . 10.1084/jem.183.4.1331 . etal.
• Coulombe R, Grochulski P, Sivaraman J . Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment. . EMBO J. . 15 . 20 . 5492–503 . 1996 . 8896443 . 452294 . 10.1002/j.1460-2075.1996.tb00934.x. etal.
• Baumgrass R, Williamson MK, Price PA . Identification of peptide fragments generated by digestion of bovine and human osteocalcin with the lysosomal proteinases cathepsin B, D, L, H, and S. . J. Bone Miner. Res. . 12 . 3 . 447–55 . 1997 . 9076588 . 10.1359/jbmr.1997.12.3.447 . 20815411 . free .
• Fujishima A, Imai Y, Nomura T . The crystal structure of human cathepsin L complexed with E-64. . FEBS Lett. . 407 . 1 . 47–50 . 1997 . 9141479 . 10.1016/S0014-5793(97)00216-0 . 46288832 . etal. free . 1997FEBSL.407...47F .
• Ménard R, Carmona E, Takebe S . Autocatalytic processing of recombinant human procathepsin L. Contribution of both intermolecular and unimolecular events in the processing of procathepsin L in vitro. . J. Biol. Chem. . 273 . 8 . 4478–84 . 1998 . 9468501 . 10.1074/jbc.273.8.4478 . etal. free .
• Schick C, Pemberton PA, Shi GP . Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis. . Biochemistry . 37 . 15 . 5258–66 . 1998 . 9548757 . 10.1021/bi972521d . etal.
• Estrada S, Nycander M, Hill NJ . The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L. . Biochemistry . 37 . 20 . 7551–60 . 1998 . 9585570 . 10.1021/bi980026r . etal.
• Halfon S, Ford J, Foster J . Leukocystatin, a new Class II cystatin expressed selectively by hematopoietic cells. . J. Biol. Chem. . 273 . 26 . 16400–8 . 1998 . 9632704 . 10.1074/jbc.273.26.16400 . etal. free .

External links

• The MEROPS online database for peptidases and their inhibitors: C01.032

Notes and References

1. Chauhan SS, Popescu NC, Ray D, Fleischmann R, Gottesman MM, Troen BR . Michael M. Gottesman . Cloning, genomic organization, and chromosomal localization of human cathepsin L . J Biol Chem . 268 . 2 . 1039–45 . Feb 1993 . 10.1016/S0021-9258(18)54038-2 . 8419312 . free .
2. Joseph LJ, Chang LC, Stamenkovich D, Sukhatme VP . Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L. An abundant transcript induced by transformation of fibroblasts . J Clin Invest . 81 . 5 . 1621–9 . Jun 1988 . 2835398 . 442598 . 10.1172/JCI113497 .
3. Web site: Entrez Gene: CTSL1 cathepsin L1.
4. Book: Barrett AJ, Kirschke H . Cathepsin B, cathepsin H, and cathepsin L . Proteolytic Enzymes, Part C . Methods in Enzymology . 80 Pt C . 535–561 . 1981 . 7043200 . 10.1016/s0076-6879(81)80043-2 . 9780121819804 .
5. Lysosomal cysteine proteinases . Barrett AJ, Buttle DJ, Mason RW . ISI Atlas of Science. Biochemistry . 1988 . 1 . 256–260 .
6. Joseph LJ, Chang LC, Stamenkovich D, Sukhatme VP . Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L. An abundant transcript induced by transformation of fibroblasts . The Journal of Clinical Investigation . 81 . 5 . 1621–1629 . May 1988 . 2835398 . 442598 . 10.1172/JCI113497 .
7. Kirschke H, Wikstrom P, Shaw E . Active center differences between cathepsins L and B: the S1 binding region . FEBS Letters . 228 . 1 . 128–130 . February 1988 . 3342870 . 10.1016/0014-5793(88)80600-8 . free . 1988FEBSL.228..128K .
8. Dickinson DP . Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease . Critical Reviews in Oral Biology and Medicine . 13 . 3 . 238–75 . 2002 . 12090464 . 10.1177/154411130201300304 .
9. Jackson CB, Farzan M, Chen B, Choe H . Mechanisms of SARS-CoV-2 entry into cells . Nature Reviews. Molecular Cell Biology . 23 . 1 . 3–20 . January 2022 . 34611326 . 8491763 . 10.1038/s41580-021-00418-x .
10. Gomes CP, Fernandes DE, Casimiro F, da Mata GF, Passos MT, Varela P, Mastroianni-Kirsztajn G, Pesquero JB . 6 . Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics . Frontiers in Cellular and Infection Microbiology . 10 . 589505 . 2022 . 33364201 . 7753008 . 10.3389/fcimb.2020.589505 . free .
11. Berdowska I, Matusiewicz M . Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis - with impact on gastrointestinal tract . World Journal of Gastroenterology . 27 . 39 . 6590–6600 . October 2021 . 34754154 . 8554394 . 10.3748/wjg.v27.i39.6590 . free .
12. 10.1016/S0003-9861(03)00319-9 . Majerle . Andreja . Jerala Roman . Sep 2003 . Protein inhibitors form complexes with procathepsin L and augment cleavage of the propeptide . Arch. Biochem. Biophys. . 417 . 1 . 53–8 . 0003-9861. 12921779 .
13. Estrada . S . Nycander M. Hill N J. Craven C J. Waltho J P. Björk I . May 1998 . The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L . Biochemistry . 37 . 20 . 7551–60 . 0006-2960. 9585570 . 10.1021/bi980026r .
14. A murrel cysteine protease, cathepsin L: bioinformatics characterization, gene expression and proteolytic activity . Venkatesh K, Prasanth B, Rajesh P, Annie JG, Mukesh P, Jesu A . Biologia . 2014 . 39 . 3 . 395–406 . 10.2478/s11756-013-0326-8. free . 2014Biolg..69..395K .
15. Sevenich L, Pennacchio LA, Peters C, Reinheckel T . Human cathepsin L rescues the neurodegeneration and lethality in cathepsin B/L double-deficient mice . Biological Chemistry . 387 . 7 . 885–91 . July 2006 . 16913838 . 10.1515/BC.2006.112 . 27739485 .