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COMPARATIVE AND EVOLUTIONARY PHYSIOLOGY

Seasonal and state-dependent changes of eIF4E and 4E-BP1 during mammalian hibernation: implications for the control of translation during torpor

¹Department of Biological Sciences, University of Nevada, Las Vegas, Nevada 89154-4004; ³Department of Cell and Developmental Biology and Molecular Biology Program, University of Colorado School of Medicine, Denver, Colorado 80262; and ²Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec H3G IY6, Canada

Submitted 24 December 2003 ; accepted in final form 24 March 2004

Mammalian hibernation involves cessation of energetically costly processes typical of homeostatic regulation including protein synthesis. To further elucidate the mechanisms employed in depressing translation, we surveyed key eukaryotic initiation factors [eIF2, eIF4B, eIF4E, eIF4GI and -II, and 4E-binding protein-1 (4E-BP1), -2, and -3] for their availability and phosphorylation status in the livers of golden-mantled ground squirrels (Spermophilus lateralis) across the hibernation cycle. Western blot analyses indicated only one significant locus for regulation of translational initiation in ground squirrel liver: control of eIF4E. We found seasonal variation in a potent regulator of eIF4E activity, 4E-BP1. Summer squirrels lack 4E-BP1 and apparently control eIF4E activity through direct phosphorylation. In winter, eIF4E is regulated through binding with 4E-BP1. During the euthermic periods that separate bouts of torpor (interbout arousal), 4E-BP1 is hyperphosphorylated to promote initiation. However, during torpor, 4E-BP1 is hypophosphorylated and cap-dependent initiation of translation is restricted. The regulation of cap-dependent initiation of translation may allow for the differential expression of proteins directed toward enhancing survivorship.

eukaryotic initiation factor 4E; 4E binding protein-1; protein synthesis

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