ИСТИНА

“Cellular IRESs” concept is predominant nowadays to explain unconventional translational properties of mammalian mRNAs, such as resistance of their translation to eIF4F inactivation under stressful conditions, mitosis, apoptosis etc. However, many cases of reported cellular IRESs have not withstood contemporary stringent tests and are apparently translated via 5’-dependent scanning. This calls for a novel interpretation of their ability to be translated under stresses. Here we show, that inserting JK-domain from EMCV IRES into 5’UTR of cap-dependent mRNA strongly enhances translation of uncapped mRNA, making its efficiency comparable to that of m7G-capped mRNA. Noteworthy, not only eIF4G-binding strongly reduced cap-dependency of translation both in vitro and in vivo, but also made translation insensitive to inhibition by 4E-BP, m7GTP or eIF4G cleavage by poliovirus 2A protease. Importantly, sole JK-domain was not sufficient to provide internal ribosome entry, as judged by its inability to function in intercistronic position. Moreover, we show that translation initiation on these mRNAs occur by ribosome scanning from the very 5’-end. Therefore, enhancers of cap-independent translation based on direct initiation factor may also operate in mammals, providing alternative paradigm to explain efficient translation of certain mRNAs under stressful conditions when cap-binding potency of translational machinery is suppressed.