5′-tRNAGly(GCC) halves generated by IRE1α are linked to ER stress response

Abstract Transfer RNA (tRNA) halves (tRHs) have various biological functions. However, the biogenesis of specific 5′-tRHs under certain conditions remains unknown. Here, we report that inositol-requiring enzyme 1α (IRE1α) cleaves the anticodon stem-loop region of tRNAGly(GCC) to produce 5′-tRHs (5′-tRH-GlyGCC) with highly selective target discrimination upon endoplasmic reticulum (ER) stress. We observed IRE1α expression-dependent 5′-tRH-GlyGCC production in human cancer cells. Levels of 5′-tRH-GlyGCC were positively correlated with the degree of cancer cell proliferation both in vitro and in vivo; this effect required co-expression of two nuclear ribonucleoproteins, HNRNPM and HNRNPH2, which we identified as binding proteins of 5′-tRH-GlyGCC. In addition, 5′-tRH-GlyGCC modulated mRNA isoform biogenesis. Furthermore, under ER stress in vivo, we observed simultaneous induction of IRE1α and 5′-tRH-GlyGCC expression in mouse organs and a distantly related organism, Cryptococcus neoformans. Thus, collectively, our findings indicate an evolutionarily conserved function for IRE1α-generated 5′-tRH-GlyGCC in cellular adaptation upon ER stress.