Annexin A6 Is a Novel Cytosolic Regulator of Multiple Inter-organelle Contact Sites

Annexins are a widely expressed family of multifunctional cytosolic proteins with diverse cellular roles. Recent advances have uncovered new avenues for the involvement of several annexins in membrane dynamics, suggesting a potential link to the coordination of membrane contact site (MCS) formation. Up to date, Annexin A1 (ANXA1), ANXA6 and ANXA11 have been defined as MCS-associated annexins. In a recent study, we demonstrated that ANXA6 critically influences the formation of multiple inter-organelle contact sites. Using electron microscopy, proximity-labelling and proteomic assays, ANXA6 deficiency was shown to substantially reduce the extent and number of MCS between several organelles in a number of cell lines. This correlated with ANXA6 interacting with various tethers and bona fide MCS proteins that can modulate multi-organelle contacts, indicating that the loss of ANXA6-related protein-protein interactions reduced the ability to develop contacts between organelles. Importantly, restoration of ANXA6 expression in ANXA6-deficient cells re-established MCS numbers, suggesting that transient changes in ANXA6 expression levels significantly impact on MCS dynamics. These findings identify ANXA6 as the first example of a cytosolic protein whose expression levels directly modulate the cellular organization of MCS.