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Updated: Sep 27, 2026
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Published on: July 16, 2019
Differential regulation of cathepsin S and cathepsin L in interferon gamma-treated macrophages
Courtney Beers1, Karen Honey, Susan Fink
1Department of Immunology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Abstract:
Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (Mphis) are unique in that they express both proteases and here we sought to determine the relative contribution of each enzyme. We observe that catL plays no significant role in Ii cleavage in interferon (IFN)-gamma-stimulated Mphis. In addition, our studies show that the level of catL activity is significantly decreased in Mphis cultured in the presence of IFN-gamma whereas catS activity increases. The decrease in catL activity upon cytokine treatment occurs despite the persistence of high levels of mature catL protein, suggesting that a specific inhibitor of the enzyme is up-regulated in IFN-gamma-stimulated peritoneal Mphis. Similar inhibition of activity is observed in dendritic cells engineered to overexpress catL. Such enzymatic inhibition in Mphis exhibits only partial dependence upon Ii and therefore, other mechanisms of catL inhibition are regulated by IFN-gamma. Thus, during a T helper cell type 1 immune response catL inhibition in Mphis results in preferential usage of catS, such that major histocompatibility complex class II presentation by all bone marrow-derived antigen-presenting cell is regulated by catS.
Insights
Interferon-gamma (IFN-γ) selectively inhibits cathepsin L (catL) activity in macrophages, promoting cathepsin S (catS) for invariant chain (Ii) degradation and MHC class II presentation.
Area of Science:
- Immunology
- Cell Biology
- Protease Function
Background:
- Cathepsin S (catS) and cathepsin L (catL) are key proteases involved in invariant chain (Ii) degradation.
- Antigen-presenting cells (APCs) utilize these enzymes for MHC class II antigen processing.
- Macrophages (Mphis) express both catS and catL, necessitating investigation into their distinct roles.
Purpose of the Study:
- To determine the relative contribution of catS and catL in Ii degradation within macrophages.
- To investigate the impact of interferon-gamma (IFN-γ) on the activity of catS and catL in Mphis.
Main Methods:
- Analysis of Ii cleavage by catS and catL in IFN-γ-stimulated Mphis.
- Measurement of catL and catS activity levels in Mphis cultured with IFN-γ.
- Investigation of catL inhibition mechanisms in Mphis and engineered dendritic cells.
Main Results:
- Cathepsin L (catL) plays a minimal role in Ii cleavage in IFN-γ-stimulated Mphis.
- IFN-γ significantly decreases catL activity while increasing catS activity in Mphis.
- CatL inhibition occurs despite high mature catL protein levels, suggesting an endogenous inhibitor is upregulated.
- Enzymatic inhibition of catL in Mphis is partially independent of Ii, indicating broader regulatory mechanisms.
Conclusions:
- IFN-γ-induced catL inhibition in Mphis leads to a preferential reliance on catS for Ii degradation.
- This shift ensures that major histocompatibility complex class II presentation by bone marrow-derived APCs is primarily regulated by catS during T helper cell type 1 immune responses.
