The Hedgehog (Hh) signaling pathway coordinates cell–cell communication in development and regeneration. Defects in this pathway underlie diseases ranging from birth defects to cancer. Hh signals are transmitted across the plasma membrane by two proteins, Patched 1 (PTCH1) and Smoothened (SMO). PTCH1, a transporter-like tumor-suppressor protein, binds to Hh ligands, but SMO, a G-protein-coupled-receptor family oncoprotein, transmits the Hh signal across the membrane. Recent structural, biochemical and cell-biological studies have converged at the surprising model that a specific pool of plasma membrane cholesterol, termed accessible cholesterol, functions as a second messenger that conveys the signal between PTCH1 and SMO. Beyond solving a central puzzle in Hh signaling, these studies are revealing new principles in membrane biology: how proteins respond to and remodel cholesterol accessibility in membranes and how the cholesterol composition of organelle membranes is used to regulate protein function.

Hedgehog (Hh) 信号通路协调发育和再生过程中的细胞间通讯。该通路的缺陷是从出生缺陷到癌症等多种疾病的基础。Hh 信号通过两种蛋白质（Patched 1 (PTCH1) 和 Smoothened (SMO)）跨质膜传递。PTCH1 是一种转运蛋白样肿瘤抑制蛋白，可与 Hh 配体结合，但 SMO（一种 G 蛋白偶联受体家族癌蛋白）可跨膜传递 Hh 信号。最近的结构、生化和细胞生物学研究集中在一个令人惊讶的模型上，即质膜胆固醇的特定库（称为可接触胆固醇）充当在 PTCH1 和 SMO 之间传递信号的第二信使。除了解决 Hh 信号传导的核心难题之外，这些研究还揭示了膜生物学的新原理：蛋白质如何响应和重塑膜中的胆固醇可及性，以及细胞器膜的胆固醇组成如何用于调节蛋白质功能。