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Updated: May 19, 2026
09:43
Measurement of Heme Synthesis Levels in Mammalian Cells
Published on: July 9, 2015
Localized heme sensing through a ternary molecular glue
Michael Heider1, Clara Hipp1,2, Zhi Yang1,2
1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
Biorxiv : the Preprint Server for Biology
|May 18, 2026
Summary
Cells use a natural molecular glue to sense and degrade toxic heme, triggering a protective gene expression response. This mechanism reveals a therapeutic vulnerability in certain leukemias, highlighting new drug development opportunities.
Area of Science:
- Molecular biology
- Biochemistry
- Cellular signaling
Background:
- Molecular glues are therapeutics that stabilize protein interactions to modify disease pathways.
- It is unknown if molecular glues can integrate additional information to orchestrate signaling beyond initial complex formation.
Purpose of the Study:
- To investigate if cells utilize an endogenous glue strategy to sense heme.
- To explore the mechanism by which heme triggers degradation of the transcriptional repressor BACH1.
- To understand the implications of this mechanism for cellular heme management and therapeutic development.
Main Methods:
- Investigated heme sensing using a ternary complex formation assay.
- Utilized protein degradation assays to study BACH1 turnover.
- Examined gene expression changes related to heme metabolism.
- Analyzed the role of cytoplasmic CUL2FEM1B in the heme-bridging mechanism.
Main Results:
- Cells employ an endogenous heme-sensing glue strategy, bridging three polypeptides.
- Heme triggers BACH1 degradation via cytoplasmic CUL2FEM1B, distinct from mitochondrial pathways.
- This mechanism induces HMOX1 expression to eliminate cytoplasmic heme while preserving mitochondrial heme.
- Ternary glue signaling presents a therapeutic vulnerability in Acute Myeloid Leukemias reliant on electron transport chain (ETC) assembly.
Conclusions:
- Endogenous molecular glues can orchestrate complex signaling beyond binary interactions.
- Heme-induced ternary complex formation provides localized cellular protection against toxic heme.
- This mechanism offers novel therapeutic strategies targeting protein proximity and degradation.
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