Mechanosensing at the endoplasmic reticulum by IRE1

Sensing and integration of mechanical forces in eukaryotic cells have largely been attributed to the plasma membrane and the nucleus. Here, we identify the endoplasmic reticulum (ER) as an autonomous mechanosensitive organelle and uncover IRE1 as an ER-resident mechanosensor. We show that applying mechanical forces to ER membranes increases lateral tension, which is sensed by the transmembrane domain of IRE1. Mechano-activation of IRE1 was unrelated to its canonical role in the unfolded protein response and occurred independently of nuclear mechanosensing. Instead, mechanically activated IRE1 triggered JNK signaling and increased global protein synthesis independently of XBP1 splicing. In engineered skeletal muscle tissue, both electrical stimulation and passive stretch similarly activated IRE1, increased translation, and contributed to training-induced increases in contractile force. Collectively, our results uncover a non-canonical role for IRE1 as an ER-based mechanosensor that couples mechanical forces to the regulation of protein translation.