Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Cell Metab. 2018 Aug 7;28(2):268-281.e4. doi: 10.1016/j.cmet.2018.05.023. Epub 2018 Jun 21.
The circadian clock coordinates behavioral and circadian cues with availability and utilization of nutrients. Proteasomal degradation of clock repressors, such as cryptochrome (CRY)1, maintains periodicity. Whether macroautophagy, a quality control pathway, degrades circadian proteins remains unknown. Here we show that circadian proteins BMAL1, CLOCK, REV-ERBα, and CRY1 are lysosomal targets, and that macroautophagy affects the circadian clock by selectively degrading CRY1. Autophagic degradation of CRY1, an inhibitor of gluconeogenesis, occurs in a diurnal window when rodents rely on gluconeogenesis, suggesting that CRY1 degradation is time-imprinted to maintenance of blood glucose. High-fat feeding accelerates autophagic CRY1 degradation and contributes to obesity-associated hyperglycemia. CRY1 contains several light chain 3 (LC3)-interacting region (LIR) motifs, which facilitate the interaction of cargo proteins with the autophagosome marker LC3. Using mutational analyses, we identified two distinct LIRs on CRY1 that exert circadian glycemic control by regulating CRY1 degradation, revealing LIRs as potential targets for controlling hyperglycemia.
生物钟协调行为和昼夜节律线索与营养物质的可用性和利用。蛋白酶体降解时钟抑制剂，如隐色素（CRY）1，维持周期性。是否自噬，一种质量控制途径，降解生物钟蛋白仍然未知。在这里，我们表明生物钟蛋白 BMAL1、CLOCK、REV-ERBα 和 CRY1 是溶酶体靶标，并且自噬通过选择性降解 CRY1 影响生物钟。作为糖异生抑制剂的 CRY1 的自噬降解发生在啮齿动物依赖糖异生的昼夜窗口中，表明 CRY1 降解是时间印记的，以维持血糖。高脂肪喂养加速自噬 CRY1 降解，并导致肥胖相关的高血糖。CRY1 含有几个 LC3 相互作用区域 (LIR) 基序，这些基序促进货物蛋白与自噬体标记 LC3 的相互作用。通过突变分析，我们在 CRY1 上鉴定了两个不同的 LIR，通过调节 CRY1 降解来发挥昼夜血糖控制作用，揭示 LIR 作为控制高血糖的潜在靶点。
