A Shift to Organismal Stress Resistance in Programmed Cell Death Mutants

Abstract

Animals have many ways of protecting themselves against stress; for example, they can induce animal-wide, stress-protective pathways and they can kill damaged cells via apoptosis. We have discovered an unexpected regulatory relationship between these two types of stress responses. We find that C. elegans mutations blocking the normal course of programmed cell death and clearance confer animal-wide resistance to a specific set of environmental stressors; namely, ER, heat and osmotic stress. Remarkably, this pattern of stress resistance is induced by mutations that affect cell death in different ways, including ced-3 (cell death defective) mutations, which block programmed cell death, ced-1 and ced-2 mutations, which prevent the engulfment of dying cells, and progranulin (pgrn-1) mutations, which accelerate the clearance of apoptotic cells. Stress resistance conferred by ced and pgrn-1 mutations is not additive and these mutants share altered patterns of gene expression, suggesting that they may act within the same pathway to achieve stress resistance. Together, our findings demonstrate that programmed cell death effectors influence the degree to which C. elegans tolerates environmental stress. While the mechanism is not entirely clear, it is intriguing that animals lacking the ability to efficiently and correctly remove dying cells should switch to a more global animal-wide system of stress resistance.

Run-on of germline apoptosis promotes gonad senescence inC. elegans

“…However, a role for molecular damage in age-related pathology in the gonad cannot be ruled out. Consistent with the latter possibility, mutation of ced-3 increases resistance to several stressors, particularly ER stress [31]. Also, molecular damage could contribute to age decline in GP rate.…”

“…Several studies suggest not: for example, lifespan was not extended either by blocking uterine tumor growth [19] or blocking apoptosis using ced-3(n1286) [20]. However, several studies have reported increases in lifespan resulting from loss of ced-3 function, either using ced-3(n717) [31], like ced-3(n1286) a strong allele [32], or ced-3 RNAi initiated at L4 [33], which suppresses only germline apoptosis. We tested both interventions, but no increase in lifespan was seen (Supplementary Figure 6A, 6B, Supplementary Table 1).…”

“…It was reported that ced-3 mutants are resistant to several stressors, and that this stress resistance is daf-16 dependent [31, 43]. This raises the possibility that suppression of gonad disintegration by ced-3(−) is due to DAF-16 activation rather than prevention of PA. We therefore tested whether suppression of gonad disintegration by ced-3 was daf-16 dependent, by subjecting daf-16(mgDf50) null mutants to ced-3 RNAi.…”

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

“…23 Moreover, pgrn-1 mutants have been reported to be refractory to ER stress-induced apoptosis measured by resistance to tunicamycin, an inhibitor of N-linked glycosylation. 24 Collectively, these findings indicate the possibility that ER stress may contribute to the regulatory role of PGRN on insulin resistance and metabolic dysfunction.…”

Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development

“…Classic cell death machinery have important non-apoptotic functions including muscle development in mammals (Fernando et al, 2002), neuronal regeneration in C. elegans (Pinan-Lucarre et al, 2012), control of longevity in C. elegans (Yee et al, 2014), stress-responsiveness in C. elegans (Judy et al, 2013), and control of stemness in mammals and C. elegans (Fujita et al, 2008; Weaver et al, 2014). Non-apoptotic caspase activity, with as-yet unknown function, has also been observed using caspase-sensitive cellular reporters in Drosophila (Tang et al, 2015).…”