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  • Review Article
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Endolysosomal proteases and their inhibitors in immunity

Nature Reviews Immunology volume 9, pages 871–882 (2009)Cite this article

Key Points

  • Proteases that are resident in, or released from, the endolysosomal system of leukocytes have important functions in the immune response.

  • Lysosome-related organelles (LROs) or granules are the main protease storage and processing organelles of the endolysosomal system. The range of proteases present in LROs is cell-type specific.

  • Endolysosomal proteolysis can involve relatively non-specific degradation, as in the formation of antigenic peptides by antigen-presenting cells, or precise cleavage events, as in the stepwise degradation of the MHC class II chaperone invariant chain.

  • Some pattern recognition receptors, such as the endosomal members of the Toll-like receptor family, TLR7 and TLR9, are activated by endolysosomal proteases.

  • Many parasites produce endolysosomal proteases of their own, which are used to facilitate host invasion or subvert the host's immune response.

  • The granzyme proteases of cytotoxic T lymphocytes are stored in LROs. They are released following fusion of the LRO with the plasma membrane and function in the killing of target cells or in immune signalling.

  • Release of proteases from LROs into the host cell cytoplasm can trigger apoptosis unless the proteases are countered by cytoplasmic protease inhibitors. Regulated release of endolysosomal proteases might contribute to leukocyte homeostasis.

Abstract

The cellular endolysosomal compartment is dynamic, complex and incompletely understood. Its organelles and constituents vary between different cell types, but endolysosomal proteases are key components of this compartment in all cells. In immune cells, these proteases function in pathogen recognition and elimination, signal processing and cell homeostasis, and they are regulated by dedicated inhibitors. Pathogens can produce analogous proteases to subvert the host immune response. The balance in activity between a protease and its inhibitor can tune the immune response or cause damage as a result of mislocalized proteolysis. In this Review, we highlight recent developments in this area and emphasize the importance of studying the role of endolysosomal proteases, and their natural inhibitors, in the initiation and regulation of immune responses.

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Figure 1: Endolysosomal proteases in pathogen detection and antigen presentation.
Figure 2: Immunomodulatory roles of parasite proteases.
Figure 3: Endolysosomal proteases and cell death.

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Acknowledgements

The authors are supported by the National Health and Medical Reseach Council, Australia. J.A.V. is a Leukemia and Lymphoma Society scholar.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia

    Phillip I. Bird

  2. Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia

    Joseph A. Trapani

  3. Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    José A. Villadangos

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A process by which fully activated T cells undergo programmed cell death following binding of the T cell receptor by antigen or mitogen.

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Bird, P., Trapani, J. & Villadangos, J. Endolysosomal proteases and their inhibitors in immunity. Nat Rev Immunol 9, 871–882 (2009). https://doi.org/10.1038/nri2671

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