Eukaryotic translation initiates upon recruitment of the EIF2-GTP·Met-tRNAi ternary complex (TC) to the ribosomes.
EIF2 (α, β, γ subunits) is a
GTPase. The
GDP to
GTP exchange within
EIF2 is facilitated by the
guanine nucleotide exchange factor EIF2B (α-ε subunits). During stress-induced conditions, phosphorylation of the α-subunit of
EIF2 turns
EIF2 into an inhibitor of
EIF2B. In turn, inhibition of
EIF2B decreases TC formation and triggers the internal stress response (ISR), which determines the cell fate. Deregulated ISR has been linked to
neurodegenerative disorders and
cancer, positioning
EIF2B as a promising therapeutic target. Hence, a better understanding of the mechanisms/factors that regulate
EIF2B activity is required. Here, combining transcript and
protein level analyses, we describe an intronically polyadenylated (IPA) transcript of
EIF2B's γ-subunit. We show that the IPA
mRNA isoform is translated into a C-terminus truncated
protein. Using structural modeling, we predict that the truncated EIF2Bγ
protein has unfavorable interactions with EIF2γ, leading to a potential decrease in the stability of the nonproductive
EIF2:
EIF2B complex. While we discovered and confirmed the IPA
mRNA isoform in
breast cancer cells, the expression of this
isoform is not
cancer-specific and is widely present in normal tissues. Overall, our data show that a truncated EIF2Bγ
protein co-exists with the canonical
protein and is an additional player to regulate the equilibrium between productive and nonproductive states of the
EIF2:
EIF2B complex. These results may have implications in stress-induced translation control in normal and disease states. Our combinatorial approach demonstrates the need to study noncanonical
mRNA and
protein isoforms to understand
protein interactions and intricate molecular mechanisms.