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.
Highlights
Lysosomes are single-membrane degradative organelles that are essential for cell homeostasis
Cathepsin K (CatK) is abundant in osteoblasts, osteoclasts, macrophages, synovial fibroblasts, and epithelial cells [5], cathepsin V (CatV) expression is restricted to the thymus and testis [6], and cathepsin S (CatS) is expressed in antigen-presenting cells (APCs) such as B cells and dendritic cells (DCs) [7]
The highest expression of cathepsin X (CatX) is detected in immune cells of myeloid lineage such as macrophages, DCs, and microglia; its expression was detected in B lymphocytes and natural killer (NK) cells [8, 9]
Summary
Lysosomes are single-membrane degradative organelles that are essential for cell homeostasis. Cysteine Cathepsins in Immune Cell Development and Function much attention in the past decades due to the critical role they play in cellular compartments other than those of the endolysosomal system and within the extracellular milieu [2]. Apart from their important roles in the immune response, such as antigen processing and presentation as well as processing and activating various proteins and hormones, cysteine cathepsins play important roles in immune cell development, regulation of the immune response and immune homeostasis, and aging of the immune system. A comprehensive review of the role of cysteine cathepsins in myeloid cell differentiation and function was published by our group recently [14] our aim is to highlight the recent developments in the field and emphasize the importance of cysteine peptidases and their endogenous and exogenous inhibitors for normal development, function and homeostasis of the lymphoid cells of the immune system
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