Institute of Development, Aging and Cancer, Tohoku University

Research

Seminars and Symposia

IDAC Seminar, 24 June 2011

Secretariat, Alumni Association, IDAC
Date Friday, 24June 2011,17:00~
Room Dai-kaigi-shitsu, IDAC Research Bldg.
Title Role of double-stranded RNA-dependent protein kinase (PKR) in metabolic disease
Speaker Takahisa Nakamura
Affiliation Harvard University
Person-in-charge Kouetsu Ogasawara Dept. Immunobiology (ex 8579)
Abstract In the past two decades, significant advances have uncovered chronic inflammation as a critical mechanism underlying a group of obesity-related metabolic diseases such as insulin resistance, type 2 diabetes, and cardiovascular disease. However, addressing critical mechanistic questions concerning the initiation and coordination of metaflammation has been challenging and how it changes metabolic homeostasis remains incompletely understood.
We recently showed that double-stranded RNA-dependent protein kinase (PKR), an established pathogen sensing protein, is involved in these critical aspects of metabolic homeostasis. Excess nutrients activate PKR, which in turn links metabolic stress signals with c-Jun N-terminal kinase (JNK), a major inflammatory signaling molecule. This PKR-JNK axis negatively regulates insulin action, at least in part, by serine-phosphorylating insulin receptor substrate (IRS) and other potential mechanisms. Intriguingly, the RNA-binding domain (RBD) of PKR is required for the stress-induced activation of PKR. These data imply that the metabolic stress affects quality and/or quantity of RNA species and these alterations maybe sensed by PKR, leading to insulin resistance and other metabolic pathologies.
More recently, our preliminary studies indicate that PKR forms complexes with several RNA-binding proteins including components of the RNA-induced silencing complex (RISC) in vivo. These observations further support our hypothesis that PKR integrates RNA species with inflammatory signaling pathways in order to regulate metabolic responses in obesity or in metabolic stress conditions such as fatty acid exposure. In this seminar, I would like to show potential roles of PKR, RNA-binding proteins, and RNA species in development of metabolic diseases and how PKR acts to coordinate multiple networks to integrate metabolism with stress signals.