An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease

• 成果类型: Article
• 署名作者: Cottle, Thomas; Joh, Lydia; Posner, Cori; DeCosta, Adam; Campagna, Dean R.; Fleming, Mark D.; Ducamp, Sarah; Kardon, Julia R.
• 署名单位: Brandeis University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ads5397
• 发表日期: 2026-07-30
• 页码: eads5397
• 关键词: LINKED DOMINANT PROTOPORPHYRIA; polymerase-delta; terminal region; synthase; mutations; binding; RECOGNITION; degradation; DISCOVERY; component

摘要

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.