Research ArticleFibrosis

Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation

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Science Signaling  12 Nov 2019:
Vol. 12, Issue 607, eaau1533
DOI: 10.1126/scisignal.aau1533

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TRPV4 and PI3Kγ cooperate to promote fibrosis

Transforming growth factor–β (TGF-β) stimulates fibroblasts to transdifferentiate into myofibroblasts that promote fibrosis. The mechanosensitive ion channel TRPV4 promotes the fibrogenic response of lung fibroblasts to TGF-β. Grove et al. found that TGF-β–driven, TRPV4-dependent transdifferentiation of human and mouse lung fibroblasts required the noncatalytic, N-terminal domain of the kinase PI3Kγ and the formation of TRPV4-PI3Kγ complexes. TRPV4 and PI3Kγ were mutually required for one another’s accumulation at the plasma membrane and for lung fibroblasts to transdifferentiate in response to TGF-β. Thus, targeting the interaction between TRPV4 and PI3Kγ may disrupt fibrogenic processes that contribute to organ fibrosis in vivo.


Myofibroblasts are key contributors to pathological fibrotic conditions of several major organs. The transdifferentiation of fibroblasts into myofibroblasts requires both a mechanical signal and transforming growth factor–β (TGF-β) signaling. The cation channel transient receptor potential vanilloid 4 (TRPV4) is a critical mediator of myofibroblast transdifferentiation and in vivo fibrosis through its mechanosensitivity to extracellular matrix stiffness. Here, we showed that TRPV4 promoted the transdifferentiation of human and mouse lung fibroblasts through its interaction with phosphoinositide 3-kinase γ (PI3Kγ), forming nanomolar-affinity, intracellular TRPV4-PI3Kγ complexes. TGF-β induced the recruitment of TRPV4-PI3Kγ complexes to the plasma membrane and increased the activities of both TRPV4 and PI3Kγ. Using gain- and loss-of-function approaches, we showed that both TRPV4 and PI3Kγ were required for myofibroblast transdifferentiation as assessed by the increased production of α-smooth muscle actin and its incorporation into stress fibers, cytoskeletal changes, collagen-1 production, and contractile force. Expression of various mutant forms of the PI3Kγ catalytic subunit (p110γ) in cells lacking PI3Kγ revealed that only the noncatalytic, amino-terminal domain of p110γ was necessary and sufficient for TGF-β–induced TRPV4 plasma membrane recruitment and myofibroblast transdifferentiation. These data suggest that TGF-β stimulates a noncanonical scaffolding action of PI3Kγ, which recruits TRPV4-PI3Kγ complexes to the plasma membrane, thereby increasing myofibroblast transdifferentiation. Given that both TRPV4 and PI3Kγ have pleiotropic actions, targeting the interaction between them could provide a specific therapeutic approach for inhibiting myofibroblast transdifferentiation.

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