Eukaryotic translation initiation factor eIF4G2 opens novel paths for protein synthesis in development, apoptosis and cell differentiation

FIGURE 1. The structures of human eIF4G protein family. (A) The domain structures of the mammalian eIF4G family. eIF4G2 lacks the N‐terminal one‐third of eIF4GI and eIF4GII, which contains the binding sites for poly(A) binding protein (PABP) and eIF4E. Domains of interaction between eIF4G and proteins are shown in coloured boxes, and their interacting proteins are labelled above the domain boxes. Each isoform of eIF4G contains three HEAT domains, with the names listed under the box. Arrows: the cleavage sites of eIF4G2. The G434 site of eIF4G2 can be cleaved by viral protease 2A, and the D792 site by caspase. (B)Protein structures of human eIF4G family. The protein structure of each eIF4G family is predicted by Alphafold2 program. 115 , 116 The HEAT‐1, HEAT‐2, and HEAT‐3 domains are shown in green, purple, and pink, respectively. The interaction domains of PABP, eIF4E and eIF3 are shown in red, blue, and orange. eIF4G2 lacks the N‐terminal binding domains for PABP and eIF4E.

FIGURE 2. Summary of the eIF4G2‐involved translation initiation. eIF4G2 supports internal ribosome entry site (IRES)‐, cap‐independent translation enhancer (CITE)‐, and N6‐methyladenosine (m6A)‐mediated translation, and promotes non‐canonical cap‐dependent translation, in which alternative proteins, like eIF3d and PARN in FXR1a‐associated microRNP‐mediated translation initiation, bind m7G cap of mRNAs. At the same time, eIF4G2 also participates in the activation of the eIF4GI‐dependent canonical cap‐dependent translation.

FIGURE 3. eIF4G2 is involved in both cap‐dependent and cap‐independent translation initiation. (A)The canonical eIF4GI‐dependent translation initiation. 40 S: the 40 S ribosomal subunit; CDS: the coding sequence; m7G: N7‐methylguanosine; 4GI: eIF4GI; 4A: eIF4A; PABP: poly(A) binding protein. eIF4GI binds to cap‐binding protein eIF4E, PABP, eIF4A and eIF3, recruiting the 40 S ribosomal subunit to initiate the translation. (B)The eIF3d‐dependent translation. 4G2: eIF4G2; 3d: eIF3d. eIF3d binds to the m7G cap of mRNA and eIF4G2 binds directly to eIF3d. Different from eIF4GI, eIF4G2 binds the eIF2β subunit. The eIF3d‐eIF4G2 complex activates the translation of some mRNAs. (C)The FXR1a‐associated microRNP‐mediated translation initiation. FXR1a: Fragile‐X‐mental‐retardation‐syndrome‐Related protein 1a. In quiescent conditions, poly(A) tails are shortened, avoiding binding to PABP. eIF4G2 is recruited to the 3′ UTRs via the interaction with microRNP containing AGO2 and FXR1a. The microRNP recruits cap‐binding protein PARN to initiate the translation. (D)eIF4G2 promotes leaky scanning through translated uORFs. uORFs: upstream open reading frames; 80 S: the 80 S ribosome. In the same uORF, eIF4GI…

FIGURE 4. Regulation of apoptosis by eIF4G2‐initiated translation. The positive regulatory events of apoptosis are shown in green, and the negative events are shown in red. When cells are stimulated by activated Fas or p53, or prolonged ER stress, the caspases are activated, leading to inhibition of cap‐dependent translation, which in turn, promotes caspase cascade and cell death. The level of eIF4G2 is maintained, and eIF4G2 can be cleaved by caspases, giving rise to an 86‐kDa fragment. Both p97 and p86 promote the eIF4G2‐initiated translation, and support translation of pro‐apoptosis proteins like c‐Myc and Apaf‐1, and of anti‐apoptosis proteins such as XIAP and HIAP2/c‐IAP1. Using this strategy, eIF4G2 regulates the balance between cell death and survival.

FIGURE 5. The role of eIF4G2 in the regulation of cell differentiation. In ESCs, eIF4G2 promotes cell differentiation by supporting the translation of HMGN3 and Map3k3. eIF4G2 also activates the translation of TUT7, a HERV‐H accumulation suppressor that inhibits neuroectoderm. Therefore, loss of eIF4G2 leads to aberrant HERV‐H expression, inhibiting neural differentiation. For immune cell differentiation, iTreg cells can be induced from human naive CD4+ T cells by mTORC1 inhibitor and TGF‐beta. When global translation is inhibited, eIF4G2 and eIF3d levels are increased, which supports the translation of Treg cell‐associated proteins like CD101 and CD103, thereby promoting cell differentiation.