5′-tRNAGly(GCC) halves generated by IRE1α are linked to the ER stress response
Hanyong Jin, Ji‐Hyun Yeom, Eunkyoung Shin, Hye‐Jeong Ha, Haifeng Liu, Daeyoung Kim, Minju Joo, Yong‐Hak Kim, Hak Kyun Kim, Minkyung Ryu, Hong-Man Kim, Jeongkyu Kim, Keun Pil Kim, Yoonsoo Hahn, Jeehyeon Bae, Kangseok Lee
Abstract
Transfer RNA 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. Levels of 5′-tRH-GlyGCC positively affect cancer cell proliferation and modulate mRNA isoform biogenesis both in vitro and in vivo; these effects require co-expression of two nuclear ribonucleoproteins, HNRNPM and HNRNPH2, which we identify as binding proteins of 5′-tRH-GlyGCC. In addition, under ER stress in vivo, we observe 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. RNA fragments derived from cleaved transfer RNAs play roles in gene regulation and cell proliferation. Here, the authors report that upon ER stress, an ER ribonuclease produces a specific tRNA fragment that promotes cancer cell proliferation and modulates mRNA alternative splicing.