CAP-BINDING PROTEIN (EUKARYOTIC INITIATION-FACTOR 4E) AND 4E-INACTIVATING PROTEIN BP-1 INDEPENDENTLY REGULATE CAP-DEPENDENT TRANSLATION

Cap-dependent protein synthesis in animal cells is inhibited by heat s hock, serum deprivation, metaphase arrest, and infection with certain viruses such as adenovirus (Ad). At a mechanistic level, translation o f capped mRNAs is inhibited by dephosphorylation of eukaryotic initiat ion factor 4E (eLF-4E) (cap-binding protein) and its physical sequestr ation with the translation repressor protein BP-1 (PHAS-I. Dephosphory lation of BP-I blocks cap-dependent translation by promoting sequestra tion of eIF-4E. Here me show that heat shock inhibits translation of c apped mRNAs bg simultaneously inducing dephosphorylation of eIF-4E and BP-1, suggesting that cells might coordinately regulate translation o f capped mRNBs bg impairing both the activity and the availability of eIF-4E. Like heat shock, late Ad infection is shown to induce dephosph orylation of eIF-4E. However, in contrast to heat shock, Ad also induc es phosphorylation of BP-1 and release of eIF-4E. BP-1 and eLF-4E can therefore act on cap-dependent translation in either a mutually antago nistic or cooperative manner, Three sets of experiments Further unders core this point: (i) rapamycin is shown to block phosphorylation of BP -1 without inhibiting dephosphorylation of eIF-4E induced by heat shoc k or Ad infection, (ii) eIF-4E is efficiently dephosphorylated during heat shock or Ad infection regardless of whether it is in a complex wi th BP-1, and (iii) BP-1 is associated with eIF-4E in vivo regardless o f the state of eIF-4E phosphorylation. These and other studies establi sh that inhibition of cap-dependent translation does not obligatorily involve sequestration of eIF-4E by BP-1. Rather, translation is indepe ndently regulated by the phosphorylation states of eIF-4E and the 4E-b inding protein, BP-1. In addition, these results demonstrate that BF-1 and eIF-4E can act either in concert or in opposition to independentl y regulate cap-dependent translation, We suggest that independent regu lation of eIF-4E and BP-1 might finely regulate the efficiency of tran slation initiation or possibly control cap-dependent translation for f undamentally different purposes.