Date Published: August , 2012
Publisher: Blackwell Publishing Ltd
Author(s): Kwame Twumasi-Boateng, Tim W Wang, Linda Tsai, Kuang-Hui Lee, Ali Salehpour, Sudarshan Bhat, Man-Wah Tan, Michael Shapira.
Stress-activated protein kinase (SAPK) pathways are evolutionarily conserved signaling modules that orchestrate protective responses to adverse environmental conditions. However, under certain conditions, their activation can be deleterious. Thus, activation of the c-Jun N-terminal kinase (JNK) SAPK pathway exacerbates a diverse set of pathologies, many of which are typical of old age. The contexts determining whether the outcome of JNK signaling is protective or detrimental are not fully understood. Here, we show that the age of an animal defines such a context. The Caenorhabditis elegans JNK homolog, KGB-1, provides protection from heavy metals and protein folding stress in developing animals. However, we found that with the onset of adulthood, KGB-1 activity becomes detrimental, reducing stress resistance and lifespan. Genetic analyses coupled with fluorescent imaging linked this phenotypic switch to age-dependent antagonistic modulation of DAF-16/FOXO: KGB-1 activation enhanced DAF-16 nuclear localization and transcriptional activity during development but decreased it in adults. Epistasis analyses showed that DAF-16 was necessary and sufficient to explain some of the kgb-1-dependent detrimental phenotypes, but not all. The identification of early adulthood as a point following which the contribution of KGB-1 activity reverses from beneficial to detrimental sheds new light on the involvement of JNK signaling in age-related pathologies. Furthermore, the age-dependent reversal has intriguing implications for our understanding of aging.
Dealing with adverse environmental perturbations is a fundamental necessity for all organisms. It is therefore not surprising that stress-activated protein kinase pathways are among the most ancient and conserved signaling modules in metazoa. The two archetypical pathways comprising this category are the p38 and the c-Jun N-terminal kinase (JNK). They are activated by a range of adverse environmental conditions, including protein folding stress, oxidative stress, and infection, and function in a typical MAPK three-tier, scaffold-protein-aided hierarchy, in which a mitogen-activated protein (MAP) kinase kinase kinase phosphorylates and activates an MAP kinase kinase, which activates either the p38 or the JNK MAP kinases, which modify the activity of numerous and diverse targets through phosphorylation (Kyriakis & Avruch, 2001; Morrison & Davis, 2003).
The dichotomy in the contribution of JNK signaling, stress protective vs. tissue damaging, is a fundamental feature of JNK signaling described in both mammals and drosophila. It is accepted that context has a dominant role in determining the outcome of JNK activation, but what defines this context(s) is not fully understood. Here, we show that age defines a context determining the outcome of JNK activation. We found that the C. elegans JNK homolog, KGB-1, protected developing larvae from heavy metals and protein folding stress but sensitized young adults to the same stressors (as well as to bacterial infection) and shortened lifespan under normal conditions. The reversal in kgb-1’s contribution was manifested following inactivation (kgb-1 knock-down) and hyperactivation (vhp-1 knock-down) alike, demonstrating that the degree of activation is secondary to the phenomenon itself and pointing at the relevance of the reversal of kgb-1 contribution to the normal C. elegans physiology.
Strains used appear in the relevant sections. A complete list appears as Supporting Information.