Induction of cap-independent BiP (hsp-3) and Bcl-2 (ced-9) translation in response to eIF4G (IFG-1) depletion inC. elegans

Abstract

During apoptosis, activated caspases cleave the translation initiation factor eIF4G. This cleavage disrupts cap-dependent mRNA translation initiation within the cell. However, a specific subset of mRNAs can still be recruited for protein synthesis in a cap-independent manner by the residual initiation machinery. Many of these mRNAs, including cell death related mRNAs, contain internal ribosome entry sites (IRESes) that promote their enhanced translation during apoptosis. Still other mRNAs have little dependence on the cap recognition mechanism. The expression of the encoded proteins, both anti- and pro-apoptotic, allows for an initial period of attempted cell survival, then commitment to cell death when damage is extensive. In this study we address the translational regulation of the stress and apoptosis-related mRNAs in C. elegans: BiP (hsp-3) (hsp-4), Hif-1 (hif-1), p53 (cep-1), Bcl-2 (ced-9) and Apaf-1 (ced-4). Altered translational efficiency of these messages was observed upon depletion of cap-dependent translation and induction of apoptosis within the C. elegans gonad. Our findings suggest a physiological link between the cap-independent mechanism and the enhanced translation of hsp-3 and ced-9. This increase in the efficiency of translation may be integral to the stress response during the induction of physiological apoptosis.

Positive mRNA Translational Control in Germ Cells by Initiation Factor Selectivity

“…Over 70% of protein synthetic capacity remains intact in “cap-independent” oocytes, but their capacity to undergo meiotic maturation (cell cycle progression) in response to progesterone is lost [ 69 , 70 ]. Similarly, the naturally occurring C. elegans IFG-1 p130 (short form) that lacks the eIF4E-binding domain supports the cap-independent initiation of housekeeping mRNAs and stress related mRNAs during germ cell apoptosis [ 71 , 72 ]. The cap-independent mechanism was originally discovered for viral mRNAs that become translated more efficiently when eIF4G is cleaved [ 73 ].…”

“…The cap-independent mechanism was originally discovered for viral mRNAs that become translated more efficiently when eIF4G is cleaved [ 73 ]. IFG p130 cap-independent translation, for example, of Hsp70 and Bcl-2 mRNAs, provides germ cells that are in distress (perhaps from meiotic DNA recombination gone wrong) with an opportunity to recover and survive during a resolution period [ 72 ]. Damage that is too severe also uses cap-independent synthesis to initiate programmed cell death, or apoptosis [ 64 , 74 ].…”

“…Germ cell deaths appear to be driven by IFG-1 p130-sustained, cap-independent translation of mRNAs that signal stress, recovery, and eventually apoptosis. Enhanced translation of the chaperone BiP ( hsp-3 ) and the apoptotic regulator Bcl-2 ( ced-9 ) mRNAs occurs in a background of less efficient translation of many “normal” mRNAs [ 72 ]. Overall, the integrated positive contributions of four selective germ cell eIF4Es and two eIF4Gs, in concert with the better-known RBP repressors, lead to a circuitry of translational control that has great latitude for mRNA types and temporal events in germ cell life ( Figure 2(a) ).…”

Cap-Independent mRNA Translation in Germ Cells

“…As a result, growth/differentiation-promoting CD translation is lost, and the remaining CI activity favors apoptotic mRNAs like Apaf-1, Bcl-2 and XIAP [20,22]. Evidence now suggests that CD and CI translation naturally co-exist in essentially all eukaryotic cells [23,24]. We do not yet know if germ cells invoke a regional distribution of CD vs. CI synthesis, but a balance between them may guide physiological processes required for attaining proper cell fates.…”

“…As more cellular CI mRNAs are discovered, it is becoming clear that many have functions unrelated to apoptosis or viral infection [38]. Their involvement in growth, signaling or stress-recovery suggests that cells “play both sides” of the cell death game using CI translation [13,16,23,29,32,38,39,40,41]. An ongoing controversy surrounds whether all these mRNAs contain canonical IRES elements because their initiation potential is not as strong as their viral counterparts [27,42].…”