TRIP6 condensates constrain Hippo pathway hyperactivation under osmotic stress
The Hippo pathway integrates mechanical and chemical cues to regulate cell proliferation and tissue homeostasis, whereas its dysregulation contributes to impaired regeneration and tumorigenesis. Liquid-liquid phase separation has emerged as an organizing principle for Hippo signal transduction, but how cells constrain excessive pathway activation under stress remain poorly defined. Here we…
TRIP6, a LIM-domain scaffold and tension-sensitive inhibitor of the Hippo pathway, has been found to form phase-separated condensates both in vitro and within living cells. When subjected to osmotic stress, these TRIP6 condensates rapidly shift from large, cortical assemblies to small, dispersed puncta within the cytoplasm. The N-terminal ID domain 2 (IDR2) is responsible for promoting TRIP6 phase separation, while the C-terminal LIM domains contribute to regulating the condensate's fluidity.
These condensates play a crucial role in selectively recruiting the LATS1 inhibitor AJUBA and the MST1 scaffold SAV1, while simultaneously excluding MST1 itself. The deficient {Delta}IDR2 mutant strain is unable to redistribute its condensates in response to stress, resulting in weakened LATS1 binding and elevated YAP phosphorylation and cytoplasmic retention. This leads to reduced cell proliferation and impaired stress resilience.
In a mouse model displaying elevated epidermal tissue tension, TRIP6 condensates disassemble, suggesting that they serve as mechanosensitive platforms that link phase transitions to Hippo-dependent growth control. Overall, these findings highlight TRIP6 condensates as a key negative regulatory node that helps maintain cellular homeostasis by buffering excessive Hippo pathway activation during hyperosmotic conditions.
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