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From CellBiology

Cathepsins - An introduction and background

Necrosis is a type of cell death which is associated with the disruption of the cell membrane leading to nuclear degradation. Normal cellular activities are deregulated when cells are exposed to extreme stress conditions such as hypoxia, disease, cancers, infarction and genetic derangement.

Proteases play a role in the degradation of the cell. Proteases are enzymes that hydrolyze peptide bonds.[1] Cathepsins are "lysosomal proteolytic enzymes"[2] which include

  • Aspartic (Cathepsins D and E)
  • Cysteine (Cathepsins B, C, H, L and S)
  • Serine (Cathepsins A and G)[3]

They are synthesized as inactive zymogens called procathepsins to protect the cell from potential disastrous consequences of uncontrolled degradation. The proenzymes are glycosylated post-translationally and travel from the Golgi apparatus towards the lysosomal compartments. Cathepsins can be released from these lysosomal compartments under certain conditions and catalyze substrate cleavage.[4]

Cathepsin enzyme localization in the cell can be viewed in stains here Cathepsin localization in necrotic cells

The cathepsin cysteine proteases belong to the papain superfamily of proteases. They include cathepsins B, C, H, L and S. The substrate specificity of these proteases are not restricted.[5] Cathepsin L is generally present in all cells in a wide range of both prokaryotes and eukaryotes.[6] It is, like other proteases, synthesized as a proenzyme called procathepsin L.

Cathepsin L Structure

Procathepsin L is a globular molecule whose mature cathepsin L part closely resembles other cysteine proteases.[7] The activation of the proenzyme does not lead to significant conformational changes in its structure. Mature Cathepsin L is made up of two domains; an alpha helical domain of Cys25 and a Beta sheet domain of His163. A specific region of its prosegment provides mannose-6-phosphate with part of the recognition site for modification; this is a signal for targetting to the lysosome.[8][9]The 3D structure of cathepsin L can be viewed here Cathepsin L 3D structure

Cathepsin L utilizes "reverse binding mode" in which enzymatic activity is inhibited by the binding of a substrate in the substrate binding cleft in reverse. This is a general mechanism for utilizing a peptide substrate and at the same time provide immunity to proteolysis. [10]

Cathepsin L roles

Cathepsin L has two cellular roles; an intracellular protein recycling role in apoptosis and an extracellular role.

  • The intracellular role of this protease lies in protein catabolism and the regulation of the intralysosomal homeostasis of the protease content.
  • The extracellular role of this cysteine protease is in the degradation of components of the extracellular matrix and basement membrane.[11] It has a high capacity to degrade extracellular matrix proteins such as collagen, laminin and elastin. [12]



Expression of Cathepsin L

The interest in Cathepsin L lies in its expression in cells. Elevated cathepsin L enzyme activity in the extracellular matrix can signify a number of gross pathological conditions[13] such as

  • Alzheimers disease
  • Cancers (Breast cancer, skin cancer, colon cancer, pancreatic cancer and lung cancer)
  • Muscle wasting
  • Autoimmune diseases such as Rheumatoid arthritis

Cancer

Cathepsin L has been identified to have significant activity in tumor-associated proteolysis for invasion and metastis in human breast cancer.[14][15] As mentioned earlier, the cysteine cathepsin L is involved in the degradation of the extracellular matrix and the basement membranes. It converts inactive pro-uPA into enzymatically active uPA which along with its inhibitor play a key role in the regulation of tumor associated proteolysis. The acidic microenvironment provides the optimum pH range for cathepsin L to carry out stroma degradation.[16]

Cathepsin L is directly related to the clinical outcome of breast cancer patients.

  • High levels of cathepsin L in primary tumours indicate an increased risk of relapse
  • Cathepsin L levels can also impact overall survival as it has been identified as an independent and strong prognostic factor comparable to other prognostic factors such as tumor size, vessel invasion, hormone receptor status and axillary lymph node status[17]

Skeletal muscle wasting

Skeletal muscle wasting can be a response to infection, injury or cancer and has a negative impact on the recovery of patients. Muscle wasting is increased by protein breakdown. Intracellular proteins can be targeted to the lysosome which is rich in cathepsins. Cathepsin L mRNA is positively regulated in muscles and a correlation between the intensity of proteolytic muscle wasting and increased cathepsin L gene expression has been noted.[18]

Cathepsin L is overexpressed in septic skeletal muscle atrophy and upregulated by glucocorticoids and tumor necrosis factor-alpha. Cathepsin L expression is induced early during sepsis. This correlates with the intensity of protein catabolism in the muscle and thus makes cathepsin L a good marker.[19] Cathepsin L has been identified as an appropriate early marker of muscle wasting in the septic phase of skeletal muscle atrophy giving it significant clinical applications.



References

  1. Cathepsin-regulated apoptosis. Chwieralski CE, Welte T, Bühling F. Apoptosis. 2006 Feb;11(2):143-9. Review.
  2. Cathepsin-regulated apoptosis. Chwieralski CE, Welte T, Bühling F. Apoptosis. 2006 Feb;11(2):143-9. Review.
  3. Cathepsin-regulated apoptosis. Chwieralski CE, Welte T, Bühling F. Apoptosis. 2006 Feb;11(2):143-9. Review.
  4. Cathepsin-regulated apoptosis. Chwieralski CE, Welte T, Bühling F. Apoptosis. 2006 Feb;11(2):143-9. Review.
  5. Cathepsin-regulated apoptosis. Chwieralski CE, Welte T, Bühling F. Apoptosis. 2006 Feb;11(2):143-9. Review.
  6. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment. Coulombe R, Grochulski P, Sivaraman J, Ménard R, Mort JS, Cygler M. EMBO J. 1996 Oct 15;15(20):5492-503.
  7. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment.Coulombe R, Grochulski P, Sivaraman J, Ménard R, Mort JS, Cygler M.EMBO J. 1996 Oct 15;15(20):5492-503.
  8. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment.Coulombe R, Grochulski P, Sivaraman J, Ménard R, Mort JS, Cygler M.EMBO J. 1996 Oct 15;15(20):5492-503.
  9. Cathepsin-regulated apoptosis. Chwieralski CE, Welte T, Bühling F. Apoptosis. 2006 Feb;11(2):143-9. Review.
  10. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment.Coulombe R, Grochulski P, Sivaraman J, Ménard R, Mort JS, Cygler M.EMBO J. 1996 Oct 15;15(20):5492-503.
  11. Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Jänicke F, Graeff H. Clin Cancer Res. 1995 Jul;1(7):741-6.
  12. Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Jänicke F, Graeff H. Clin Cancer Res. 1995 Jul;1(7):741-6.
  13. http://www.metachem.co.uk/Cathepsin.htm
  14. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment. Coulombe R, Grochulski P, Sivaraman J, Ménard R, Mort JS, Cygler M. EMBO J. 1996 Oct 15;15(20):5492-503.
  15. Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Jänicke F, Graeff H. Clin Cancer Res. 1995 Jul;1(7):741-6.
  16. Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Jänicke F, Graeff H. Clin Cancer Res. 1995 Jul;1(7):741-6.
  17. Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer. Thomssen C, Schmitt M, Goretzki L, Oppelt P, Pache L, Dettmar P, Jänicke F, Graeff H. Clin Cancer Res. 1995 Jul;1(7):741-6.
  18. Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting.Deval C, Mordier S, Obled C, Bechet D, Combaret L, Attaix D, Ferrara M.Biochem J. 2001 Nov 15;360(Pt 1):143-50.
  19. Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting.Deval C, Mordier S, Obled C, Bechet D, Combaret L, Attaix D, Ferrara M.Biochem J. 2001 Nov 15;360(Pt 1):143-50.