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Frolova, A.S.; Chepikova, O.E.; Deviataikina, A.S.; Solonkina, A.D.; Zamyatnin, A.A. Role of Nuclear Proteases in Cell Death Pathways. Encyclopedia. Available online: (accessed on 22 June 2024).
Frolova AS, Chepikova OE, Deviataikina AS, Solonkina AD, Zamyatnin AA. Role of Nuclear Proteases in Cell Death Pathways. Encyclopedia. Available at: Accessed June 22, 2024.
Frolova, Anastasia S., Olga E. Chepikova, Anna S. Deviataikina, Alena D. Solonkina, Andrey A. Zamyatnin. "Role of Nuclear Proteases in Cell Death Pathways" Encyclopedia, (accessed June 22, 2024).
Frolova, A.S., Chepikova, O.E., Deviataikina, A.S., Solonkina, A.D., & Zamyatnin, A.A. (2023, June 17). Role of Nuclear Proteases in Cell Death Pathways. In Encyclopedia.
Frolova, Anastasia S., et al. "Role of Nuclear Proteases in Cell Death Pathways." Encyclopedia. Web. 17 June, 2023.
Role of Nuclear Proteases in Cell Death Pathways

Multiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, others remain poorly characterized. Regulation of nuclear protease activity is a promising therapeutic strategy that could selectively induce favorable cell death pathways in specific tissues or organs.

protease nucleus cell death apoptosis

1. Introduction

Multicellular organisms are comprised of individual cells acting in tight and regulated cooperation. The development of an organism involves numerous rounds of cell division, but the number of cell divisions is limited, and as a result, the cell that gave rise to a large population dies. Cell death is the final stage in the life of a cell [1]. In some cases, cell death is delayed or, conversely, occurs prematurely. Tumor cells can avoid cell death, thereby replacing healthy tissues and migrating throughout the body [2]. In the case of neurodegenerative diseases, an increase in the occurrence of cell death is observed [3]. Therefore, a complete understanding of the mechanisms of cell death will provide an opportunity to find new options for the treatment of many diseases.
Every compartment in the cell has its own distinct function, with the nucleus serving as a crucial hub for genetic information storage and processing. The nucleus is responsible for controlling numerous cellular functions, including gene expression, DNA replication, and repair. One of the most significant changes that occurs during cell death is the alteration of chromatin structure, DNA degradation, and disassembly of nuclear structural proteins [4][5].
The destruction of nuclear and other proteins is accomplished by proteases, which hydrolyze peptide bonds between amino acids. Proteases are traditionally divided into specific groups according to the type of reaction they catalyze, amino acids in the active center, structure, and other features [6]. The key role of proteases is the ability to cleave proteins and thereby control individual protein levels. This allows proteases to participate in the regulation of many cellular processes, such as cell proliferation and differentiation [7], DNA replication, transcription and repair [8], angiogenesis and extracellular matrix remodeling [9][10], immunity [11][12], cell death [13], etc. Proteases are also involved in pathological conditions. In cancer, proteases regulate proteolytic extracellular matrix (EMC) remodeling, altering cell–cell and cell–matrix interactions that facilitate invasion and metastasis [14][15][16][17][18].
Proteases have been identified in the nucleus [19][20][21]. These proteases play a significant role in the regulation of gene expression [22][23], as well as in the immune response, carcinogenesis [24], and cell death [25]. Recent research has revealed that proteases in the nucleus perform a variety of functions, which include processing and activation of transcription factors, chromatin remodeling, histone modification, and DNA repair. Proteases also play a role in maintaining the structural integrity of the nucleus. The activity of nuclear proteases is tightly regulated to ensure the proper functioning of the cell. Dysregulation of these enzymes can lead to a wide range of diseases, including cancer or neurodegenerative disorders.

2. Nuclear Proteases

Proteases participate in many cellular processes, in which it is necessary to cleave proteins in the extracellular matrix, on the cellular membrane or in some cellular compartments. In many cases, proteases have either a specific localization, such as on the membrane [26], or their localization in cells change due to different factors [27]
Proteases that are secreted into the extracellular environment or anchored in the cell membrane can affect morpho- and angiogenesis by remodeling the extracellular matrix [9][10]. Acidic vesicles, known as lysosomes, contain pH-dependent proteases—cathepsins, napsins, and asparagine endopeptidase [28]. These lysosomal proteases are responsible for protein degradation during phagocytosis, endocytosis, and autophagy, but are also involved in growth factor signaling, and antigen presentation. Mitoproteases, which are found in mitochondria, degrade misfolded or damaged proteins, regulate mitochondrial gene expression and mitophagy, and activate or inhibit a number of other pathways [28].
Research indicates that nuclear proteases may exhibit high specificity towards nuclear proteins. For instance, nuclear cathepsins have been observed to cleave specific nuclear substrates, while lysosomal cathepsins can cleave all available proteins [29]. This specificity presents an exciting opportunity to use nuclear proteases for cleaving specific proteins, potentially modulating cell death by degrading key proteins. Furthermore, nuclear proteases might be utilized for the degradation of unwanted accumulated proteins, such as polyglutamine proteins that are associated with neuropathology [30]. Targeted degradation of these proteins using nuclear proteases could be a promising approach for treatment. Studying the nuclear substrates of nuclear proteases could also provide insight into utilizing them in targeting systems such as PROTACs (proteolysis targeting chimeras) for specific degradation of nuclear proteins [31]. The potential applications of nuclear proteases are vast, but careful study of these proteins is required to fully understand their functions and potential. Understanding the mechanism of action of nuclear proteases, their specificity, and the consequences of their activity will be critical in developing effective therapies and treatments that can harness their potential. Future research should continue to explore the role of nuclear proteases in cellular processes and their potential applications in therapeutic interventions.
Many proteases exhibit both nuclear and cytoplasmic localization, and it remains unclear why certain proteases translocate into the nucleus. Detailed analysis of protein sequences has revealed that some proteases possess a nuclear translocation signal (NLS). For example, matrix metalloproteinase-2 (MMP-2) has an NLS on its C-terminus, and amino acid substitutions in this region result in loss of nuclear localization [32]. Bioinformatic analysis of MMP proteins has shown that all members of this group contain one or more NLSs [21]. However, not all of these proteases have been found in the nucleus, indicating that the presence of an NLS alone may not be sufficient for nuclear translocation. The localization of the NLS within the protein structure plays an important role in determining its localization. In some cases, the NLS may be masked by a prodomain or linker region, preventing the protein from translocating into the nucleus [25]. Given these findings, the mechanisms that dictate whether proteases in their active or inactive forms exhibit nuclear localization are still not fully understood. Further research is necessary to elucidate the factors that influence nuclear translocation of proteases, which could have significant implications for understanding their regulation.

3. Nuclear Compartment in Cell Death

The nucleus is a defining feature of eukaryotic cells and is the largest organelle in most cells. It separates the genome and transcriptional machinery from the cytoplasm [33]. The nucleus serves as the cell’s control center by coordinating processes such as cell growth, metabolism, and cell division. In addition, the nucleus plays a role in some forms of cell death.
There are different classifications and nomenclatures of cell death, based on multiple mechanisms and phenotypes. Historically, three morphologically distinct categories (type I-III cell death), namely apoptosis, autophagy, and necrosis, have been used for classification [34][35]. This morphological classification is still extensively employed. In 2018, the Nomenclature Committee on Cell Death provided molecular marker-based definitions of cell death types. Intrinsic and extrinsic apoptosis are types of cell death that occur in response to internal or external signals. Mitochondrial permeability transition (MPT)-driven necrosis is caused by mitochondrial destruction, while necroptosis and parthanatos are mediated by specific proteins. Iron overload and lipid peroxidation are the triggers for ferroptosis, whereas pyroptosis, entotic cell death, NETosis, and immunogenic cell death are types of cell death that occur as a consequence of an inflammatory response. Two types of cell death involve specific compartments harboring various proteases, namely lysosome-dependent cell death and autophagy-dependent cell death. Cellular senescence is a form of cell death that occurs due to a state of cell division arrest, and mitotic catastrophe happens when cells perform an abortive act of cell division. Cell death can happen in two ways: due to overwhelming damage, which is called accidental cell death, or as a result of specific signaling events, also known as regulated cell death (RCD), which is the physiological form of programmed cell death [36][37]. Among all the mentioned types of cell death, only three occur with the participation of the cell nucleus: apoptosis, parthanatos, and NETosis.
Apoptosis is a multi-pathway mode of cell death that leads to the destruction of cells and the nucleus plays a crucial role in this process. The intrinsic pathway of apoptosis is initiated by internal signals, including DNA damage, which triggers the release of cytochrome c from mitochondria. The regulation of this pathway is carried out by pro- and anti-apoptotic proteins of the BCL-2 family, as well as initiator and effector caspases [38][39]. The activation of initiator caspases by cytochrome c in turn activates the main effector caspases. In contrast, extrinsic signals activate a distinct apoptosis pathway, which ultimately leads to the activation of effector caspases. Once translocated into the nucleus, effector caspases cleave several nuclear proteins, including poly(ADP-ribose) polymerase-1 (PARP-1), lamin, β-tubulin, and others [40]. Cleavage of the inhibitor of caspase-activated DNase (ICAD) by caspase-3 is a crucial event in the apoptotic pathway, allowing caspase-activated DNase (CAD) to induce oligonucleosomal DNA fragmentation [41][42][43]. Other mitochondrial proteins, such as endonuclease G (EndoG) and apoptosis-inducing factor (AIF), also enter the nucleus and initiate chromatin condensation and DNA fragmentation, which can later lead to membrane blebbing. In the final stages of apoptosis, the cell partitions into small apoptotic bodies that are eliminated by macrophages or surrounding cells. In that case, the contents of the cell is not released into the environment and does not trigger an inflammatory reaction.
Parthanatos is a distinct type of cell death that is mainly triggered by DNA damage. In response to this, PARP-1 protein begins to produce an excessive amount of poly(ADP-ribose) (PAR), which is then translocated into the mitochondria. The PAR molecules interact with the mitochondria, inducing the release of AIF [44]. Once AIF enters the nucleus, it triggers extensive DNA fragmentation and chromatin condensation, ultimately leading to cell death. The translocation of AIF from mitochondria to the nucleus, and subsequent nucleus destruction, which is characteristic of this type of cell death, highlights the critical role of the nucleus in parthanatos [45].
NETotic cell death is thought to involve a complex signaling pathway [46][47][48]. Activation of NADPH oxidase by chemical reagents or bacterial action leads to the formation of reactive oxygen species (ROS) [46]. The presence of ROS triggers the release of bactericidal proteins, such as antimicrobial peptides, cytokines, and digestive enzymes, including neutrophil elastase (NE), cathepsin G, azurocidin, and myeloperoxidase (MPO), from the azurophilic granules of neutrophils into the cytosol [49]. NE partially translocates into the nucleus and cleaves nuclear proteins [50]. Peptidyl arginine deiminase 4 (PAD4) also enters the nucleus, where it induces histone citrullination [51][52], leading to DNA decondensation. In the next stage of NETosis, decondensed chromatin, decorated with histones and antimicrobial proteins, is released into the cytoplasm as a result of rupturing of the nuclear envelope. This forms a net-like structure, termed the neutrophil extracellular trap (NET), which is then expelled from the cell [46]. The nucleus’s involvement in NETotic cell death underscores the significance of this compartment in cell death mechanisms.
The cell death mechanisms in the nucleus share a similar pattern across the three types of cell death: apoptosis, NETosis, and parthanatos (Figure 1). During apoptosis and parthanatos, DNA condensation occurs through the common protein AIF, while NETosis involves DNA decondensation, which is critical for NET formation. DNA fragmentation is exclusive to apoptosis. These three cell death types also involve disruption of the nuclear envelope to a varying degree. For example, in apoptosis, nuclear proteases cleave lamins, which leads to destruction of the nuclear envelope and the nucleus as a whole [53][54]. During NETosis, pores form in the nuclear envelope, possibly due to the insertion of gasdermin D protein into the membrane [55]. Disassembly of nuclear lamin without proteolysis is also observed [56]. The process of nuclear destruction during parthanatos has not been extensively studied, and the proteins that are responsible for this process remain unknown.
Figure 1. Role of nucleus in three types of cell death: apoptosis, NETosis and parthanatos. Although these cell death pathways have different activators, the nuclear events that occur during these processes are similar. This includes the degradation of structural and functional proteins by proteases, as well as DNA decondensation or degradation by endonucleases or modification enzymes. Apoptosis proteins are indicated in blue boxes; NETosis—pink, parthanatos—green.
All these processes involve important nuclear regulatory proteins in the cell nucleus. Apoptosis demonstrates how the degradation of such proteins by nuclear proteinases can regulate cell death (Table 1). The pathways of NETosis and parthanatos are not yet fully understood, and there are many gaps in our knowledge of the nucleus’s role in these processes that may involve the action of nuclear proteases.
Table 1. Nuclear substrates in apoptosis, parthanatos, and NETosis.
Cell Death Protease Substrate in Nucleus Substrate Cell Function What Happened after Cleavage Ref.
apoptosis caspase-3 Sp1 Transcription factor Apoptosis [57]
PARP-1 DNA repair Activation of apoptosis [58]
lamin Nuclear envelope Degradation of nucleus [53]
importin-α Import of protein in cell nucleus Downregulate DNA synthesis [59]
large subunit of the DNA replication complex C Regulation of DNA replication Decrease DNA binding [60]
Rad51 DNA repair Activation of apoptosis [61]
ICAD Inhibition of CAD DNA fragmentation [42][62]
calpain lamin A Nuclear envelope Degradation of nucleus [54]
lamin B Nuclear envelope Degradation of nucleus [54]
spectrin Skeletal protein Product of SBPD145, 150i, 120
Activation of apoptosis
cathepsin L p53 Transcription factor, regulation
of caspase-7 expression
Silencing of CtsL induce the decrease in p53 [64]
prohibitin Transcription factor, regulation
of caspase-7 expression
Silencing of CtsL induce the decrease in p53 [64]
cathepsin B - - DNA condensation and fragmentation [65]
granzyme lamin Nuclear envelope - [66]
PARP DNA repair - [67][68]
ICAD Inhibition of CAD - [67]
- - DNA fragmentation [69]
?—apoptosis calpain PARP DNA repair - [70]
CaMK4 Calcium signaling, regulates β-cell apoptosis - [71]
β-catenin Transcription factor, regular expression of Wnt pathways genes - [72]
c-Fos Transcription factor - [73][74]
c-Jun Transcription factor - [73][74]
Sp3, Sp4 Transcription factor - [75]
p53 Transcription factor - [76]
SPase Sp1 Transcription factor - [77]
Rb Regulates cell growth - [77]
NETosis calpain H3 Maintains structure of DNA Degradation of nuclear envelope [78]
HP1a Gene regulation Chromatin decondensation [78]
lamin A/C Nuclear core structure Degradation of nuclear envelope [78]
H3 Maintains structure of DNA Degradation of nuclear envelope [78]
? ? Chromatin decondensation [78]
neutrophil elastase H1, H2A, H2B, H3, H3 Maintains structure of DNA Chromatin decondensation [50][79]
?—parthanatos calpain PARP - - [70]
granzyme PARP - - [67]
cysteine protease/cathepsin AIF - - [64][80]
?—The involvement in cell death based on the substrate.


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