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- W2885456907 abstract "Transforming growth factor-β (TGFβ) signaling through SMAD2/3 is an important driver of pathological fibrosis in multiple organ systems. TGFβ signaling and extracellular matrix (ECM) stiffness form an unvirtuous pathological circuit in which matrix stiffness drives activation of latent TGFβ, and TGFβ signaling then drives cellular stress and ECM synthesis. Moreover, ECM stiffness also appears to sensitize cells to exogenously activated TGFβ through unknown mechanisms. Here, using human fibroblasts, we explored the effect of ECM stiffness on a putative inner nuclear membrane protein, LEM domain–containing protein 3 (LEMD3), which is physically connected to the cell's actin cytoskeleton and inhibits TGFβ signaling. We showed that LEMD3–SMAD2/3 interactions are inversely correlated with ECM stiffness and TGFβ-driven luciferase activity and that LEMD3 expression is correlated with the mechanical response of the TGFβ-driven luciferase reporter. We found that actin polymerization but not cellular stress or LEMD3–nuclear-cytoplasmic couplings were necessary for LEMD3–SMAD2/3 interactions. Intriguingly, LEMD3 and SMAD2/3 frequently interacted in the cytosol, and we discovered LEMD3 was proteolytically cleaved into protein fragments. We confirmed that a consensus C-terminal LEMD3 fragment binds SMAD2/3 in a stiffness-dependent manner throughout the cell and is sufficient for antagonizing SMAD2/3 signaling. Using human lung biopsies, we observed that these nuclear and cytosolic interactions are also present in tissue and found that fibrotic tissues exhibit locally diminished and cytoplasmically shifted LEMD3–SMAD2/3 interactions, as noted in vitro. Our work reveals novel LEMD3 biology and stiffness-dependent regulation of TGFβ by LEMD3, providing a novel target to antagonize pathological TGFβ signaling. Transforming growth factor-β (TGFβ) signaling through SMAD2/3 is an important driver of pathological fibrosis in multiple organ systems. TGFβ signaling and extracellular matrix (ECM) stiffness form an unvirtuous pathological circuit in which matrix stiffness drives activation of latent TGFβ, and TGFβ signaling then drives cellular stress and ECM synthesis. Moreover, ECM stiffness also appears to sensitize cells to exogenously activated TGFβ through unknown mechanisms. Here, using human fibroblasts, we explored the effect of ECM stiffness on a putative inner nuclear membrane protein, LEM domain–containing protein 3 (LEMD3), which is physically connected to the cell's actin cytoskeleton and inhibits TGFβ signaling. We showed that LEMD3–SMAD2/3 interactions are inversely correlated with ECM stiffness and TGFβ-driven luciferase activity and that LEMD3 expression is correlated with the mechanical response of the TGFβ-driven luciferase reporter. We found that actin polymerization but not cellular stress or LEMD3–nuclear-cytoplasmic couplings were necessary for LEMD3–SMAD2/3 interactions. Intriguingly, LEMD3 and SMAD2/3 frequently interacted in the cytosol, and we discovered LEMD3 was proteolytically cleaved into protein fragments. We confirmed that a consensus C-terminal LEMD3 fragment binds SMAD2/3 in a stiffness-dependent manner throughout the cell and is sufficient for antagonizing SMAD2/3 signaling. Using human lung biopsies, we observed that these nuclear and cytosolic interactions are also present in tissue and found that fibrotic tissues exhibit locally diminished and cytoplasmically shifted LEMD3–SMAD2/3 interactions, as noted in vitro. Our work reveals novel LEMD3 biology and stiffness-dependent regulation of TGFβ by LEMD3, providing a novel target to antagonize pathological TGFβ signaling." @default.
- W2885456907 created "2018-08-22" @default.
- W2885456907 creator A5005975889 @default.
- W2885456907 creator A5009267693 @default.
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- W2885456907 creator A5029727630 @default.
- W2885456907 creator A5033029316 @default.
- W2885456907 creator A5047779503 @default.
- W2885456907 creator A5073026508 @default.
- W2885456907 date "2018-10-01" @default.
- W2885456907 modified "2023-10-15" @default.
- W2885456907 title "LEM domain–containing protein 3 antagonizes TGFβ–SMAD2/3 signaling in a stiffness-dependent manner in both the nucleus and cytosol" @default.
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- W2885456907 doi "https://doi.org/10.1074/jbc.ra118.003658" @default.
- W2885456907 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6187619" @default.
- W2885456907 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30108174" @default.
- W2885456907 hasPublicationYear "2018" @default.
- W2885456907 type Work @default.