Resumen de Modificaciones de la maquinaria de iniciacion de la traduccion por proteasas retrovirales

Enrique Álvarez Gómez

• The initiation of translation plays an important role in the regulation of gene expression in mammalian cells. The translation initiation factor eIF4G, attached to eIF4E and eIF4A, constitutes the eIF4F complex which is a key component to promote the binding of ribosomes to mRNAs. eIF4G has emerged as a key target for the regulation of translation in mammalian cells infected with different viruses. Thus, cleavage of eIF4G by viral proteases from picornaviruses, as well as from human immunodeficiency virus type 1 (HIV-1), leads to inhibition of protein synthesis directed by capped cellular mRNAs. Notably, this cleavage of eIF4G does not hamper translation directed by mRNAs containing an internal ribosome entry site (IRES) structure.

  In the present work, cleavage of both eIF4GI and eIF4GII has been examined with the proteases encoded within the genomes of several members of the family Retroviridae, e.g., Moloney murine leukemia virus (MoMLV), mouse mammary tumor virus, human T-cell leukemia virus type 1, HIV-2, and simian immunodeficiency virus. All retroviral proteases examined were capable to cleave the initiation factor eIF4GI both in intact cells and in cell-free systems, albeit with different efficiencies. The pattern obtained from the hydrolysis of eIF4GI with HIV-1 and HIV-2 proteases were very similar to each other, but differed from that obtained with MoMLV protease. Both eIF4GI and eIF4GII were cleaved very efficiently by the MoMLV protease.

  Notably, eIF4GII was a poor substrate for HIV proteases. Proteolytic cleavage of eIF4G by retroviral proteases led to a profound inhibition of cap-dependent translation, while protein synthesis driven by mRNAs containing IRES elements remained unaffected or was even stimulated in transfected cells and in cell-free systems. Our present findings illustrating those retroviral proteases hydrolyze eIF4G point to the idea that these viruses may follow a mechanism similar to that described for picornav