Endoplasmic Reticulum Proteins Regulate Organelle Distribution; Change in Function May Treat Neurologic Disease
- The endoplasmic reticulum (ER) spreads throughout the cytoplasm of eukaryotes in association with microtubules and makes abundant contacts with other organelles; when ER positioning is disrupted, the proper distribution of other organelles is affected
- Dysregulation of ER morphology has been closely linked to neurologic disease and cancer
- Researchers at Massachusetts General Hospital identified three ER proteins—kinectin, p180 and CLIMP63—that differentially maintain proper ER distribution, which regulates organelle distribution
- Fine-tuning of molecular interactions to change ER positioning and function may someday have therapeutic applications in neurologic diseases
In eukaryotes, the positioning of organelles such as the nucleus, mitochondria and lysosomes is critical for their proper function. Organelles are transported along microtubules, and the ability of microtubules to distribute organelles properly relies on multiple post-translational microtubule modifications that comprise part of the "tubulin code."
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Strict regulation of intracellular organelle transport and distribution is especially important in specialized cell types, including neurons. Craig Blackstone, MD, PhD, chief of the Movement Disorders Division in the Department of Neurology at Massachusetts General Hospital and a physician investigator in the Mass General Research Institute, Pengli Zheng, PhD, postdoctoral fellow, and colleagues have discovered that proteins in the endoplasmic reticulum (ER) decipher the tubulin code to regulate organelle positioning. They published their report in Nature.
The researchers zeroed in on the ER because it spreads throughout the cytoplasm in association with microtubules and makes abundant contacts with other organelles. When ER positioning is disrupted, the distributions of other organelles is affected. Notably, dysregulation of ER shaping has been closely linked to neurogenerative diseases and cancer.
Three membrane-bound proteins—kinectin, p180 and CLIMP63—localize prominently to dense, sheet-like perinuclear ER, and each of them binds microtubules. However, the phenotypes of cells that lack these proteins differ considerably, raising the question of how microtubule binding selectivity is maintained.
Key Study Findings
The new study explains the differential effects of the absence of the three proteins. The researchers determined those proteins interact with different microtubule populations:
- Kinectin preferentially bound perinuclear polyglutamylated microtubules
- p180 robustly bound both mono- and polyglutamylated microtubules
- CLIMP63 bound centrosome microtubules and was relatively insensitive to changes in microtubule glutamylation
Knockout of these proteins or manipulation of microtubule populations and glutamylation status resulted in marked changes in ER positioning and similar redistribution of other organelles.
It may be that "fine-tuning" of molecular interactions could improve ER function and restore proper organelle position in patients with disease. For example, modifying the number of glutamates added to tubulin side chains may exert a substantial effect on ER distribution and subsequently the positioning and function of other organelles
It's likely other ER-localized, microtubule-binding proteins will be found to contribute to overall cellular ER positioning, which may have additional therapeutic implications.
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