The squirrel with the lagging eIF2: Global suppression of protein synthesis during torpor

Hibernating mammals use strong metabolic rate depression and a reduction in body temperature to near-ambient to survive the cold winter months. During torpor, protein synthesis is suppressed but can resume during interbout arousals. The current study aimed to identify molecular targets responsible for the global suppression of protein synthesis during torpor as well as possible mechanisms that could allow for selective protein translation to continue over this time. Relative changes in protein expression and/or phosphorylation levels of key translation factors (ribosomal protein S6, eIF4E, eIF2α, eEF2) and their upstream regulators (mTOR, TSC2, p70 S6K, 4EBP) were analyzed in liver and kidney of 13-lined ground squirrels (Ictidomys tridecemlineatus) sampled from six points over the torpor-arousal cycle. The results indicate that both organs reduce protein synthesis during torpor by decreasing mTOR and TSC2 phosphorylation between 30 and 70% of control levels. Translation resumes during interbout arousal when p-p70 S6K, p-rpS6, and p-4EBP levels returned to control values or above. Only liver translation factors were activated or disinhibited during periods of torpor itself, with >3-fold increases in total eIF2α and eEF2 protein levels, and a decrease in p-eEF2 (T56) to as low as 16% of the euthermic control value. These data shed light on a possible molecular mechanism involving eIF2α that could enable the translation of key transcripts during times of cell stress.