IKKβ activation promotes amphisome formation and extracellular vesicle secretion in tumor cells.

Xueqiang Peng, Liang Yang, Yingbo Ma, Xinyu Li, Shuo Yang, Yan Li, Bo Wu, Shilei Tang, Fuhui Zhang, Bing Zhang, Jingang Liu, Hangyu Li

Biochimica et biophysica acta. Molecular cell research 2021 Jan

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Intracellular organelle cross-talk is a new and important research area. Under stress conditions, the coordinated action of the autophagy and endosomal systems in tumor cells is essential for maintaining cellular homeostasis and survival. The activation of the IκB kinase (IKK) complex is also involved in the regulation of stress and homeostasis in tumor cells. Here, we try to explore the effects of constitutively active IKKβ subunits (CA-IKKβ) on autophagy and endosomal system interactions. We confirm that CA-IKKβ induces accumulation of autophagosomes and their fusion with MVBs to form amphisomes in cancer cells, and also drives the release of EVs containing autophagy components through an amphisome-dependent mechanism. We further demonstrate that CA-IKKβ inhibits the expression of RAB7, thereby weakening the lysosomal-dependent degradation pathway. CA-IKKβ also induces phosphorylation of SNAP23 at Ser95 instead of Ser110, which further promotes amphisome-plasma membrane fusion and sEV secretion. These results indicate that CA-IKKβ drives the formation and transport of amphisomes, thereby regulating tumor cell homeostasis, which may illuminate a special survival mechanism in tumor cells under stress. Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Xueqiang Peng, Liang Yang, Yingbo Ma, Xinyu Li, Shuo Yang, Yan Li, Bo Wu, Shilei Tang, Fuhui Zhang, Bing Zhang, Jingang Liu, Hangyu Li. IKKβ activation promotes amphisome formation and extracellular vesicle secretion in tumor cells. Biochimica et biophysica acta. Molecular cell research. 2021 Jan;1868(1):118857