Long-term autophagy is sustained by activation of CCTβ3 on lipid droplets

Yuta Ogasawara, Jinglei Cheng, Tsuyako Tatematsu, Misaki Uchida, Omi Murase, Shogo Yoshikawa, Yuki Ohsaki and Toyoshi Fujimoto ()
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Yuta Ogasawara: Juntendo University Graduate School of Medicine
Jinglei Cheng: Nagoya University Graduate School of Medicine
Tsuyako Tatematsu: Nagoya University Graduate School of Medicine
Misaki Uchida: Nagoya University Graduate School of Medicine
Omi Murase: Nagoya University Graduate School of Medicine
Shogo Yoshikawa: Nagoya University Graduate School of Medicine
Yuki Ohsaki: Nagoya University Graduate School of Medicine
Toyoshi Fujimoto: Juntendo University Graduate School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Macroautophagy initiates by formation of isolation membranes, but the source of phospholipids for the membrane biogenesis remains elusive. Here, we show that autophagic membranes incorporate newly synthesized phosphatidylcholine, and that CTP:phosphocholine cytidylyltransferase β3 (CCTβ3), an isoform of the rate-limiting enzyme in the Kennedy pathway, plays an essential role. In starved mouse embryo fibroblasts, CCTβ3 is initially recruited to autophagic membranes, but upon prolonged starvation, it concentrates on lipid droplets that are generated from autophagic degradation products. Omegasomes and isolation membranes emanate from around those lipid droplets. Autophagy in prolonged starvation is suppressed by knockdown of CCTβ3 and is enhanced by its overexpression. This CCTβ3-dependent mechanism is also present in U2OS, an osteosarcoma cell line, and autophagy and cell survival in starvation are decreased by CCTβ3 depletion. The results demonstrate that phosphatidylcholine synthesis through CCTβ3 activation on lipid droplets is crucial for sustaining autophagy and long-term cell survival.

Date: 2020
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DOI: 10.1038/s41467-020-18153-w

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