Cathepsins: Key modulators of cell death and inflammatory responses

Abstract

Apoptosis is a key mechanism in the build up and maintenance of both innate and adaptive immunity as well as in the regulation of cellular homeostasis in almost every organ and tissue. Central to the apoptotic process is a family of intracellular cysteine proteases with aspartate-specificity, called caspases. Nevertheless, there is growing evidence that other non-caspase proteases, in particular lysosomal cathepsins, can play an important role in the regulation of apoptosis. In this review, the players and the molecular mechanisms involved in the lysosomal apoptotic pathways will be discussed as well as the importance of these pathways in the immune system and the pathogenesis of diseases.

Introduction

The immune system is a remarkably adaptive defense mechanism that has evolved in vertebrates to protect them from invading infectious agents and to repair damaged tissue. It is able to generate an enormous variety of cells and molecules capable of specifically recognizing and eliminating an apparently unlimited variety of foreign invaders. Although accumulation of these specialized cells and molecules at inflammatory sites helps to efficiently eliminate invading agents, it may also amplify the inflammatory response by damaging surrounding tissue [1]. Therefore, mechanisms are needed to tightly control the number of inflammatory cells, in particular under inflammatory conditions, during which stimulated cells are releasing toxic mediators.

Apoptosis, or programmed cell death, is an innate mechanism by which an organism eliminates such unwanted and potentially harmful cells from inflamed tissues without releasing hazardous intracellular contents [2], [3]. In contrast to necrosis, apoptosis is the most physiological form of cell death [4], [5]. Apoptotic cells die via two main pathways: the extrinsic and the intrinsic apoptotic pathways. The intrinsic pathway is triggered by a whole variety of intracellular stress signals such as growth factor withdrawal, aberrant calcium flux, viral infection, oxidative stress, UV radiation or cytotoxic agents, mediating mitochondrial outer membrane permeabilization (MOMP) which in turn induces the release of apoptogenic factors from the intermitochondrial space in order to activate downstream effectors. The extrinsic apoptotic pathway is induced by ligand-mediated stimulation of members belonging to the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily of cell-surface ‘death receptors’ (e.g. Fas/CD95, TNF-receptor I or TNFRI). These receptors contain, within their cytoplasmic region, a functional death domain (DD) which is able, via adapter proteins, to trigger an autocatalytic activation cascade leading to apoptosis.

For both pathways, the central component is a proteolytic cascade involving proteases called caspases. Caspases are a family of evolutionarily conserved cysteinyl proteases mediating initiation and execution of apoptosis through aspartate-specific cleavage of a wide number of cellular substrates [6]. This very specific cleavage either activates their substrates, such as certain apoptosis-related endonucleases and protein kinases, or inactivates them, such as anti-apoptotic proteins, transcription factors, mRNA splicing proteins, translation initiators, or cytoskeletal components [7].

Besides caspases, another family of proteases, namely cathepsins, has recently been shown to be associated with cell death regulation [8], [9], [10], [11]. Although cathepsins have often been considered as intracellular proteases capable of mediating caspase-independent cell death [8], there is also evidence that they act in concert with caspases in apoptotic cell death. In this review, we will discuss the role of cathepsins in caspase-dependent and -independent apoptotic pathways and hypothesize that lysosomes, in which cathepsins are located within healthy cells, could be a new therapeutic target in immune responses by regulating the life span of inflammatory cells like neutrophils and T or B cells. In addition, we will review a panel of molecules which are able to either permeabilize or stabilize the lysosomal membrane, such as certain chemotherapeutic drugs, reactive oxygen species (ROS), Bcl-2 family members and heat shock proteins.