Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis.
As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient- and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, we provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction.
Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Takahisa
T
Nakamura
Masato
M
Furuhashi
Ping
P
Li
Haiming
H
Cao
Gurol
G
Tuncman
Nahum
N
Sonenberg
Cem Z
CZ
Gorgun
Gökhan S
GS
Hotamisligil
D000818:Animals; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism*; D051379:Mice; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D019892:eIF-2 Kinase; D048670:MAP Kinase Kinase 4