Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing

Science. 2024 Dec 20;386(6728):1427-1434. doi: 10.1126/science.adp9388. Epub 2024 Dec 19.

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.

MeSH terms

  • 5-Aminolevulinate Synthetase* / genetics
  • 5-Aminolevulinate Synthetase* / metabolism
  • Animals
  • Argonaute Proteins* / genetics
  • Argonaute Proteins* / metabolism
  • HEK293 Cells
  • Heme* / metabolism
  • Hepatocytes* / metabolism
  • Humans
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • RNA Interference
  • RNA, Small Interfering* / genetics
  • RNA, Small Interfering* / metabolism

Substances

  • 5-Aminolevulinate Synthetase
  • ALAS1 protein, human
  • Argonaute Proteins
  • Heme
  • MicroRNAs
  • RNA, Small Interfering