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3C Protease as Ferroptosis Inducer
Regulated cell death (RCD) is a fundamental process common to nearly all living beings and essential for the development and tissue homeostasis in animals and humans. A wide range of molecules can induce RCD including a number of viral proteolytic enzymes. To date, numerous data indicate that picornaviral 3C proteases can induce RCD. In most reported cases, these proteases induce classical caspase-dependent apoptosis. In contrast, the human hepatitis A virus 3C protease (3Cpro) has recently been shown to cause caspase-independent cell death accompanied by previously undescribed features.
In the current topic the results of the study where 3Cpro-induced cell death was characterized morphologically and biochemically are presented. It was found that dead cells demonstrated necrosis-like morphological changes including permeabilization of plasma membrane, loss of mitochondrial potential, as well as mitochondria and nuclei swelling. Additionally, it was shown that 3Cpro-induced cell death was efficiently blocked by ferroptosis inhibitors and was accompanied by intense lipid peroxidation. Taken together, these results indicate that 3Cpro induces ferroptosis upon its individual expression in human cells. This is the first demonstration that a proteolytic enzyme can induce ferroptosis, the recently discovered and actively studied type of RCD.
2. Ectopic Expression of 3Cpro and Its Inactive Form 3Cmut in Human Cells
3. 3Cpro Expression Induces Caspase-Independent Cell Death with Cytoplasmic Vacuolization
4. Cells Expressing 3Cpro Acquire Necrotic Morphology and Are Characterized by Nuclei and Mitochondria Swelling
5. 3Cpro-Induced Cell Death Is Effectively Blocked by Ferroptosis Inhibitors and Is Accompinied by Lipid Peroxidation
However, the data obtained are not enough to establish the biological role of 3Cpro as a ferroptosis inducer. It is common knowledge that human hepatitis A virus has no direct cytopathic effect on hepatocytes, although the liver is the primary locus of virus replication. In vivo the main factor that damages the liver is the death of infected hepatocytes mainly due to the activity of cytotoxic T cells and natural killer cells . Moreover, the intracellular level of 3Cpro is apparently much lower during the infection compared to that in our experimental system. In this context, it is likely that 3Cpro affects certain cell substrates to maintain viral replication in vivo, while ferroptosis induction is a side effect of 3Cpro action. Apparently, low cellular levels of 3Cpro have no such side effect, while higher protease levels in our experimental system can induce it. A detailed analysis of the molecular mechanism of 3Cpro-induced cell death is needed to reveal the relationship between the ability of 3Cpro to induce ferroptosis and the viral life cycle. In the first place, the cellular targets of 3Cpro should be identified. This information can also extend our knowledge about the mechanism and biological role of ferroptosis.
The entry is from 10.3390/ijms22157906
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