ER proteins decipher the tubulin code to regulate organelle distribution

Pengli Zheng (), Christopher J. Obara, Ewa Szczesna, Jonathon Nixon-Abell, Kishore K. Mahalingan, Antonina Roll-Mecak, Jennifer Lippincott-Schwartz and Craig Blackstone ()
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Pengli Zheng: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Christopher J. Obara: Howard Hughes Medical Institute
Ewa Szczesna: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Jonathon Nixon-Abell: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Kishore K. Mahalingan: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Antonina Roll-Mecak: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Jennifer Lippincott-Schwartz: Howard Hughes Medical Institute
Craig Blackstone: National Institute of Neurological Disorders and Stroke, National Institutes of Health

Nature, 2022, vol. 601, issue 7891, 132-138

Abstract: Abstract Organelles move along differentially modified microtubules to establish and maintain their proper distributions and functions1,2. However, how cells interpret these post-translational microtubule modification codes to selectively regulate organelle positioning remains largely unknown. The endoplasmic reticulum (ER) is an interconnected network of diverse morphologies that extends promiscuously throughout the cytoplasm3, forming abundant contacts with other organelles4. Dysregulation of endoplasmic reticulum morphology is tightly linked to neurologic disorders and cancer5,6. Here we demonstrate that three membrane-bound endoplasmic reticulum proteins preferentially interact with different microtubule populations, with CLIMP63 binding centrosome microtubules, kinectin (KTN1) binding perinuclear polyglutamylated microtubules, and p180 binding glutamylated microtubules. Knockout of these proteins or manipulation of microtubule populations and glutamylation status results in marked changes in endoplasmic reticulum positioning, leading to similar redistributions of other organelles. During nutrient starvation, cells modulate CLIMP63 protein levels and p180–microtubule binding to bidirectionally move endoplasmic reticulum and lysosomes for proper autophagic responses.

Date: 2022
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DOI: 10.1038/s41586-021-04204-9

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