Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing Journal Article
| Authors: | Lee, S.; Lee, S.; Desnick, R.; Yasuda, M.; Lai, E. C. |
| Article Title: | Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing |
| Abstract: | microRNAs (miRNAs) and small interfering RNAs (siRNAs) are 21- to 22-nucleotide RNAs that guide Argonaute-class effectors to targets for repression. In this work, we uncover 5-aminolevulinic acid synthase 1 (ALAS1), the initiating enzyme for heme biosynthesis, as a general repressor of miRNA accumulation. Although heme is known to be a positive cofactor for the nuclear miRNA processing machinery, ALAS1-but not other heme biosynthesis enzymes-limits the assembly and activity of Argonaute complexes under heme-replete conditions. This involves a cytoplasmic role for ALAS1, previously considered inactive outside of mitochondria. Moreover, conditional depletion of ALAS activity from mouse hepatocytes increases miRNAs and enhances siRNA-mediated knockdown. Notably, because ALAS1 is the target of a Food and Drug Administration-approved siRNA drug, agents that suppress ALAS may serve as adjuvants for siRNA therapies. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; hepatocytes; microrna; small interfering rna; rna, small interfering; rna interference; liver cell; micrornas; argonaute protein; hek293 cells; heme; argonaute proteins; humans; human; hek293 cell line; 5 aminolevulinate synthase; 5-aminolevulinate synthetase; alas1 protein, human |
| Journal Title: | Science |
| Volume: | 386 |
| Issue: | 6728 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2024-12-20 |
| Start Page: | 1427 |
| End Page: | 1434 |
| Language: | English |
| DOI: | 10.1126/science.adp9388 |
| PUBMED: | 39700288 |
| PROVIDER: | scopus |
| PMCID: | PMC11829814 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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