Fig. 4: ER stress-independent functions of the UPR.

a | IRE1α and PERK localize to endoplasmic reticulum (ER)–mitochondrion contact sites that form structures known as mitochondria-associated membranes (MAMs). PERK regulates reactive oxygen species (ROS) propagation under ER stress at MAMs, in addition to affecting ER-to-mitochondrion tethering through the interaction with mitofusin 2 (MFN2). PERK also associates with filamin A (FLNA) to regulate ER–plasma membrane contact sites and calcium entry into the cell through ORAI–stromal interaction molecule (STIM) channels. The activity and stability of IRE1α is differentially regulated at MAMs through interaction with σ₁ receptor (SIG-1R). IRE1α also docks the inositol 1,4,5-trisphosphate receptor (IP₃R) at MAMs to control the transfer of calcium into the mitochondria and the activation of the tricarboxylic acid (TCA) cycle to produce ATP. b | Cell migration is regulated by IRE1α and PERK through the direct binding of filamin A, a regulator of actin cytoskeleton dynamics. IRE1α recruits protein kinase Cα (PKCα) as a scaffold to trigger filamin A phosphorylation, leading to its activation as a crosslinker of actin filaments. c | Plasma membrane receptor signalling pathways undergo crosstalk with unfolded protein response (UPR) signalling by leading to the activation of UPR sensors in an ER stress-independent manner. In addition, genotoxic stress might trigger a non-canonical activation of IRE1α to trigger regulated IRE1-dependent decay (RIDD) and modulate the DNA damage response. d | Cell-non-autonomous UPR activation. Expression of spliced X-box-binding protein 1 (XBP1s) in neurons signals for distal tissues to activate IRE1α−XBP1 and drive proteostatic changes that control healthspan and lifespan in simple model organisms such as Caenorhabditis elegans. XBP1s regulates different cellular processes to extend healthspan, including lipophagy, lysosomal function, proteostasis and lipid production. Neurotransmitter release mediates non-autonomous signalling downstream of XBP1s, suggesting that a secreted ER stress signal (SERSS) promotes ER stress resistance and longevity. BCR, B cell receptor; BDNF, brain-derived neurotrophic factor; GPCR, G protein-coupled receptor; mTORC1, mTOR complex 1; PKA, protein kinase A; PLCγ, phospholipase Cγ; PP2A, protein phosphatase 2A; TLR, Toll-like receptor; UFM1, ubiquitin-fold modifier 1, VDAC, voltage-dependent anion-selective channel; VEGFR, vascular endothelial growth factor receptor.