Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism

Keren E. Shapira, Marcelo Ehrlich*, Yoav I. Henis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor-β (TGF-β) plays critical roles in numerous physiological and pathological responses. Cholesterol, a major plasma membrane component, can have pronounced effects on signaling responses. Cells continually monitor cholesterol content and activate multilayered transcriptional and translational signaling programs, following perturbations to cholesterol homeostasis (e.g., statins, the commonly used cholesterol-reducing drugs). However, the cross-talk of such programs with ligand-induced signaling responses (e.g., TGF-β signaling) remained unknown. Here, we studied the effects of a mild reduction in free (membrane-associated) cholesterol on distinct components of TGF-β-signaling path-ways. Our findings reveal a new regulatory mechanism that enhances TGF-β-signaling responses by acting downstream from receptor activation. Reduced cholesterol results in PKR-dependent eIF2α phosphorylation, which enhances c-Jun translation, leading in turn to higher levels of JNK-mediated c-Jun phosphorylation. Activated c-Jun enhances transcription and expression of Smad2/3. This leads to enhanced sensitivity to TGF-β stimulation, due to increased Smad2/3 expression and phosphorylation. The phospho/total Smad2/3 ratio remains unchanged, indicating that the effect is not due to altered receptor activity. We propose that cholesterol depletion induces overactivation of PKR, JNK, and TGF-β signaling, which together may contribute to the side effects of statins in diverse disease settings.

Original languageEnglish
Pages (from-to)2494-2507
Number of pages14
JournalMolecular Biology of the Cell
Volume29
Issue number20
DOIs
StatePublished - 1 Oct 2018

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