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      The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function

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          Abstract

          Cysteine cathepsins are primarily involved in the degradation and recycling of proteins in endo-lysosomal compartments but are also gaining recognition as pivotal proteolytic contributors to various immune functions. Through their extracellular proteolytic activities within the hematopoietic stem cell niche, they are involved in progenitor cell mobilization and differentiation. Cysteine cathepsins, such as cathepsins L and S contribute to antigen-induced adaptive immunity through major histocompatibility complex class II antigen presentation whereas cathepsin X regulates T-cell migration. By regulating toll-like receptor signaling and cytokine secretion cysteine cathepsins activate innate immune cells and affect their functional differentiation. Cathepsins C and H are expressed in cytotoxic T lymphocytes and natural killer cells and are involved in processing of pro-granzymes into proteolytically active forms. Cytoplasmic activities of cathepsins B and L contribute to the maintenance of homeostasis of the adaptive immune response by regulating cell death of T and B lymphocytes. The expression pattern, localization, and activity of cysteine cathepsins is tightly connected to their function in immune cells. Furthermore, cysteine cathepsins together with their endogenous inhibitors, serve as mediators in the interplay between cancer and immune cells that results in immune cell anergy. The aim of the present article is to review the mechanisms of dysregulation of cysteine cathepsins and their inhibitors in relation to immune dysfunction to address new possibilities for regulation of their function.

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          Most cited references253

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          NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?

          The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that activates caspase 1, leading to the processing and secretion of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18. The NLRP3 inflammasome is activated by a wide range of danger signals that derive not only from microorganisms but also from metabolic dysregulation. It is unclear how these highly varied stress signals can be detected by a single inflammasome. In this Opinion article, we review the different signalling pathways that have been proposed to engage the NLRP3 inflammasome and suggest a model in which one of the crucial elements for NLRP3 activation is the generation of reactive oxygen species (ROS).
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            Lysosomal membrane permeabilization in cell death.

            Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.
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              Adult haematopoietic stem cell niches

              Recent advances in imaging techniques and genetic tools have rapidly increased our understanding of the niches that maintain adult haematopoietic stem cells, including the constituent cell types and the factors that directly or indirectly regulate these niches.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                15 July 2021
                2021
                : 12
                : 680279
                Affiliations
                [1] 1 Department of Biotechnology, Jožef Stefan Institute , Ljubljana, Slovenia
                [2] 2 Faculty of Pharmacy, University of Ljubljana , Ljubljana, Slovenia
                Author notes

                Edited by: Dipnarine Maharaj, Maharaj Institute of Immune Regenerative Medicine, United States

                Reviewed by: Takashi Nagasawa, Osaka University, Japan; Jonilson Berlink Lima, Federal University of Western Bahia, Brazil; Roi Gazit, Ben Gurion University of the Negev, Israel

                *Correspondence: Milica Perišić Nanut, milica.perisic@ 123456ijs.si

                This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.680279
                8322073
                34335582
                e1bce138-dd46-496b-8238-1641b3772d74
                Copyright © 2021 Perišić Nanut, Pečar Fonović, Jakoš and Kos

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 March 2021
                : 01 July 2021
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 253, Pages: 19, Words: 10573
                Funding
                Funded by: Javna Agencija za Raziskovalno Dejavnost RS 10.13039/501100004329
                Categories
                Immunology
                Review

                Immunology
                cysteine cathepsins,cystatins,hematopoietic stem cell,immune cell development,extralysosomal activity

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