Cysteine protease cathepsin B mediates radiation-induced bystander effects

Abstract

Radiation-induced bystander effects (RIBE) refer to a unique process, in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses, and altered apoptosis or cell proliferation1–3. Despite important implications in radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain elusive. Here we use C. elegans as an animal model to study RIBE and have identified a cysteine protease CPR-4, a human cathepsin B homolog, as the first RIBE factor in nematodes. CPR-4 is secreted from animals irradiated with ultraviolet (UV) or ionizing gamma rays (IR) and is the major factor in the conditioned medium that leads to inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress response at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homolog cep-1 in response to radiation and CPR-4 appears to act through the insulin-like growth factor receptor, DAF-2, to exert RIBE. Our study provides critical insights into the elusive RIBE and will facilitate identification of additional RIBE factors and their mechanisms of action.

A genetic program mediates cold-warming response and promotes stress-induced phenoptosis in C. elegans

“…However, unlike other stress-responding TFs that activate genes largely beneficial for physiological homeostasis and thus animal health under stress conditions ( Baird et al, 2014 ; Dempersmier et al, 2015 ; Hwang and Lee, 2011 ; Kandror et al, 2004 ; Kumsta et al, 2017 ; Landis and Murphy, 2010 ), identified transcriptional targets of ZIP-10 include at least two Cathepsin-type proteases, CPR-3 and ASP-17 ( Figure 4E ). In contrast to aspartyl-type proteases which are largely unknown in cellular functions, caspase-type proteases are well-known apoptotic cell death executioners while CPR-4, a Cathepsin CPR-3 paralogue, has been shown to inhibit cell deaths in C. elegans ( Metzstein et al, 1998 ; Peng et al, 2017 ; Peter, 2011 ). Ectopic expression of zip-10 and its targets promotes organismic deaths, in contrast to the effect of zip-10 or asp-17 deficiency on cold tolerance ( Figure 5E and F ).…”

Linking cellular stress responses to systemic homeostasis

“…CPR-4 release was associated with reduced cell death in the non-irradiated tissues and neighbouring animals, as well as with larval lethality. Subsequently, CPR-4 was mechanistically identified as the factor responsible for these radiation-induced bystander effects 46 . This mechanism is an interesting example of intracellular adaptation to stress relaying a signal not only to the entire organism but also to other individuals.…”

Quercetin and Its Mixture Increase the Stress Resistance of Caenorhabditis elegans to UV-B

“…Subsequently, this operation was repeated twice. These C. elegans laid eggs for a total of 12 h at 25 • C. After 24 h at 25 • C, non-hatched eggs (dead eggs) were counted on all NGM plates [23].…”