线粒体蛋白酶介导血红素生物合成反馈调节的衔接蛋白
线粒体蛋白酶介导血红素生物合成反馈调节的衔接蛋白
作者： 小柯机器人 发布时间：2026/7/31 16:44:54
本期文章：《科学》：Volume 393 Issue 6810
美国布兰迪斯大学Julia R. Kardon团队宣布他们提出线粒体蛋白酶介导血红素生物合成反馈调节的衔接蛋白。相关论文发表在2026年7月30日出版的《科学》杂志上。
研究小组发现聚合酶δ相互作用蛋白2 （POLDIP2）是一种血红素感应接头蛋白，足以重建CLPXP对ALAS的负反馈降解。在红细胞生成过程中，POLDIP2对于支持细胞中ALAS的转换和调节血红素的产生是必需的。POLDIP2直接识别并招募结合血红蛋白的ALAS到CLPXP。降解起始需要ALAS的羧基末端元件，其截断会引起红细胞原卟啉症。他们的发现建立了CLPXP条件降解的机制，该机制是与CLPX和ALAS相关的红细胞原卟啉症的基础。
据悉，血红素的生物合成是紧密协调的，以支持基本功能，而不积累有毒的卟啉和消耗细胞铁。血红素诱导线粒体酪蛋白水解蛋白酶复合物CLPX-CLPP （CLPXP）降解血红素生物合成酶5-氨基乙酰酸合成酶（ALAS），但其降解机制尚未阐明。
附：英文原文
Title: An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease
Author: Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Dean R. Campagna, Mark D. Fleming, Sarah Ducamp, Julia R. Kardon
Issue&Volume: 2026-07-30
Abstract: Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
DOI: ads5397
Source: https://www.science.org/doi/10.1126/science.ads5397