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Aging, Metabolism, Stress, Pathogenesis, and Small RNAs in C. elegans Topic Meeting 2012
A New Class of Stress Resistance Genes
Aimee Kao, Ayumi Nakamura, Meredith Judy, Anne Huang, Cynthia Kenyon
University of California San Francisco, San Francisco, CA
Animals have many ways of protecting themselves against stress; for example, they can
induce stress-protective pathways or they can kill damaged cells via apoptosis. How the
choice between these different options is made is not well understood. Here we show that C.
elegans mutations that block the normal course of programmed cell death confer resistance
to a specific set of environmental stressors: heat, ER and osmotic stress. Surprisingly, ced-3
caspase mutations that block apoptosis; ced-1 and other engulfment mutations that prevent
apoptotic cell removal, and progranulin (pgrn-1) mutations that accelerate dying cell removal,
all increased stress resistance. Because it is a gene that is associated with multiple diseases
in humans, including neurodegeneration, auto-immunity and cancer, we characterized pgrn-1
mutant-associated stress resistance in detail. We found that the ER stress resistance elicited
by pgrn-1 mutations exhibits genetic dependency on the unfolded protein response (UPR)
factors IRE-1 and PEK-1, the MAP kinase PMK-1 and the stress-related transcription factor
DAF-16/FOXO. Mutations in pgrn-1 and the ced genes may induce a common pathway, since
they do not exhibit additive effects. To explain these findings, we propose that C. elegans has a
surveillance system that detects perturbations in the normal cell death pathway and responds
to them by inducing an alternative, organism-wide stress-protective pathway. These genes
represent a new class of stress response regulators.
Contact: akao@memory.ucsf.edu
Lab: Kenyon/Kao
28
Session 4