The RING domains of the promyelocytic leukemia protein PML and the arenaviral protein Z repress translation by directly inhibiting translation initiation factor eIF4E

The promyelocytic leukemia protein (PML) is a mammalian regulator of cell g rowth which is characteristically disrupted in acute promyelocytic leukemia and by a variety of viruses. PML contains a RING domain which is required for its growth-suppressive and antiviral properties. Although normally nucl ear, in certain pathogenic conditions, including arenaviral infection, PML is relocated to the cytoplasm, where its functions are poorly understood. H ere, we observe that PML and arenavirus protein Z use regions around the fi rst zinc-binding site of their respective RING domains to directly interact , with sub-micromolar affinity, with the dorsal surface of translation init iation factor eIF4E, representing a novel mode of eIF4E recognition. PML an d Z profoundly reduce the affinity of eIF4E for its substrate, the 5' 7-met hyl guanosine cap of mRNA, by over 100-fold. Association with the dorsal su rface of eIF4E and direct antagonism of mRNA cap binding by PML and Z lead to direct inhibition of translation. These activities of the RING domains o f PML and Z do not involve ubiquitin-mediated protein degradation, in contr ast to many RINGs which have been observed to do so. Although PML and Z hav e well characterized physiological functions in regulation of growth and ap optosis, this work establishes the first discrete biochemical mechanism whi ch underlies the biological activities of their RING domains. Thus, we esta blish PML and Z as translational repressors, with potential contributions t o the pathogenesis of acute promyelocytic leukemia and variety of viral inf ections. (C) 2001 Academic Press.