Intracellular Role for the Matrix-Modifying Enzyme Lox in Regulating Transcription Factor Subcellular Localization and Activity in Muscle Regeneration

Integration of extracellular matrix (ECM)-derived cues into transcriptional programs is essential primarily in rapidly morphing environments, such as regenerating tissues. Here, we demonstrate that lysyl oxidase (Lox), known for its ECM-modifying activities, primarily collagen crosslinking, also directly regulates transcription factor (TF) localization. Using genetic and pharmacological strategies, we highlight an intracellular role for Lox in myogenic progenitors essential for muscle regeneration. We show that Lox interacts with, and directly oxidizes, vestigial-like 3 (Vgll3), a transcriptional co-activator acting with Mef2 and transcriptional enhancer factor (TEF) TFs. This enzymatic activity is required for Vgll3 cytoplasmic-to-nuclear translocation in regulation of myogenic differentiation. Our work highlights an additional mechanism for TF subcellular localization facilitating integration of ECM organization with transcriptional output during myogenic differentiation. Modulating this integration mechanism could affect the balance between ECM organization and cell differentiation and serve as a basis for novel therapeutic strategies targeting fibrotic pathologies. Lox is best known as a secreted ECM-modifying enzyme and is upregulated upon muscle injury. Yehezkely et al. found that in myogenic progenitors cytoplasmic Lox autonomously regulates myogenic differentiation. Lox binds and oxidizes Vgll3, a TF involved in myogenic differentiation, regulating the dynamics of Vgll3 cytoplasm-to-nucleus translocation.