Regulatory mechanisms affecting metabolic homeostasis and aging

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  • 2017-01-06


[2016 Fall Life Sciences & IBB Regular Seminar]
                  ▶Subject: Regulatory mechanisms affecting metabolic homeostasis and aging
                  ▶Speaker: Prof. Keith Blackwell
                    (Joslin Diabetes Center, Harvard Medical School)

                  ▶Date: 4:30PM/Oct. 10(Mon.)/2016
                  ▶Place: Auditorium(1F), Postech Biotech Center
                  For many years reactive oxygen species (ROS) were thought simply to cause damage, and to be a major driver of aging, but recently it has become apparent that ROS induce mobilization of protective mechanisms that increase lifespan. Moreover, an emerging body of evidence suggests the existence of an exciting landscape of normal biological regulation that is mediated by ROS signals, and cysteine (Cys) modifications. The extent and functional versatility of this signaling remain unclear, however.
 The endoplasmic reticulum (ER) transmembrane protein IRE-1 maintains ER homeostasis by initiating the unfolded protein response (UPRER). Working in C. elegans and human cells, we have determined that IRE-1 has a distinct, unexpected, and conserved redox-regulated function in cytoplasmic homeostasis. When reactive oxygen species (ROS) are produced in the vicinity of IRE-1, a conserved Cys that is located within its cytoplasmic kinase activation loop become sulfenylated (SH to SOH). This modification inhibits the IRE-1-mediated UPRER, and initiates the p38/SKN-1(Nrf2) antioxidant response at IRE-1. This IRE-1/p38 signaling can be triggered by ROS that are produced by mitochondria, by an IRE-1-associated oxidase in response to stress, or by the ER itself. ER-generated ROS extend C. elegans lifespan robustly through this mechanism, dependent upon the protective action of SKN-1. This pathway is conserved in humans, in which it mediates Nrf2 activation by particular stimuli. Many AGC-family kinases (AKT, p70S6K, PKC, ROCK1) seem to be regulated similarly, suggesting possible coordination of ROS-responsive effects.
 IRE-1 therefore not only protects the ER against accumulation of unfolded proteins, but also has an ancient sentinel function as a ROS signal sensor that controls SKN-1/Nrf2. This paradigm illustrates how Cys modifications from localized ROS signals may have inhibitory, activating, or neomorphic effects on protein function, and identifies the ER as a source of ROS signals that influence aging. While these signals can drive longevity extension, it is also likely that perturbation of ROS/Cys signaling networks during disease and aging could be deleterious

              ▶Inquiry: Prof. Seung-Jae Lee (279-2351)
                    * This seminar will be given in English.
                please refrain from taking photos during seminars. *