VAPB and its binding partner AKAP11 promote lipid droplet degradation

Borst Pauwels, S.; Spits, M.; Janssen, L. L. J.; Rotman, S.; de Ru, A. H.; de Jong, A. W. M.; Bos, E.; van Veelen, P. A.; Koning, R. I.; Giera, M.; Neefjes, J.; Cabukusta, B.

doi:10.64898/2026.01.27.699657

bioRxiv · 10.64898/2026.01.27.699657

VAPB and its binding partner AKAP11 promote lipid droplet degradation

Borst Pauwels, S.·Spits, M.·Janssen, L. L. J.·Rotman, S.·de Ru, A. H.·de Jong, A. W. M.·Bos, E.·van Veelen, P. A.·Koning, R. I.·Giera, M.·Neefjes, J.·Cabukusta, B.

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Abstract

The endoplasmic reticulum (ER) is the master regulator of various cellular processes. To achieve its diverse functions, the ER interacts with other organelles at membrane contact sites, regions where organelles are brought into proximity. Most ER membrane contact sites are facilitated by the ER-resident VAP proteins. To address the role of VAP proteins in regulating cellular lipid homeostasis, we performed a targeted lipidomic screen after silencing individual VAPs. The loss of VAPB increases cellular levels of neutral lipids stored in lipid droplets (LDs). The increase in neutral lipids is reflected in the size, number and motility of LDs, and is due to the impaired degradation of these organelles. VAPB requires its contact site forming ability to regulate LDs, prompting the identification of protein kinase A (PKA) anchor AKAP11 as a VAPB interaction partner in regulating LD degradation and dynamics. Collectively, our findings identify a role for the ER-resident VAPB-AKAP11 interaction and PKA activity in regulating LD homeostasis. SummaryThe ER-resident membrane contact site protein VAPB and its interaction partner AKAP11 regulate lipid droplet size and motility by mediating neutral lipid degradation. VAPB requires its ability to form membrane contact sites and interact with AKAP11, protein kinase A anchor protein, for mediating lipid droplet homeostasis. This paper uncovers a role for VAPB-AKAP11-PKA axis in regulating the homeostasis of lipid droplets.

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Borst Pauwels, S., Spits, M., Janssen, L. L. J., Rotman, S., de Ru, A. H., de Jong, A. W. M., Bos, E., van Veelen, P. A., Koning, R. I., Giera, M., Neefjes, J., Cabukusta, B.. 2026-01-27. VAPB and its binding partner AKAP11 promote lipid droplet degradation. https://doi.org/10.64898/2026.01.27.699657

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