Abstract
The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. Here we find that loss of Mst1/2, the mammalian Hippo orthologues, or their regulator WW45, leads to a remarkably enlarged endoplasmic reticulum (ER) size-associated UPR. Intriguingly, attenuation of the UPR by tauroursodeoxycholic acid (TUDCA) diminishes Mst1/2 mutant-driven liver overgrowth and tumorigenesis by promoting nuclear exit and degradation of Hippo downstream effector Yap. Yap is required for UPR activity and ER expansion to alleviate ER stress. During the adaptive stage of the UPR, PERK kinase-eIF2α axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Significantly, the deregulation of UPR signals associated with Yap activation is found in a substantial fraction of human hepatocellular carcinoma (HCC). Thus, we conclude Yap integrates Hippo and UPR signalling to control liver size and tumorigenesis.
Highlights
The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown
We uncovered a physiological role of Yes-associated protein (Yap) in maintaining endoplasmic reticulum (ER) homeostasis and demonstrated that the synergistic effects of Hippo signalling and PKR-like ER kinase (PERK) branch of the UPR are critical for cell fate determination during ER stress, in which the induction and activation of Yap is the key event (Fig. 9j)
WW45-deficient livers exhibited greatly enhanced UPRs, resulting in gradually increased levels of Yap expression that depended on the induction of PERK signalling, which is required for cell survival[58]
Summary
The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. During the adaptive stage of the UPR, PERK kinase-eIF2a axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Different ER stress transducers located on the ER membrane, such as PKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), can initiate distinct UPR signalling pathways. During the adaptive stage of ER stress, the phosphorylation of eIF2a at serine 51 by PERK suppresses general protein synthesis and induces the translation of ATF4 to promote cell survival[5]. X-box binding protein 1 (Xbp1) messenger RNA is induced by ATF6 and spliced by IRE1 in response to ER stress, to produce a highly active transcription factor (Xbp1s), which is critical for cell fate determination in response to ER stress[6]. The dephosphorylation of Yap by PP1 results in its nuclear accumulation[14], thereby promoting cell proliferation and inhibiting cell death via the TEAD transcription factor
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