Annexin A7 is required for ESCRT III-mediated plasma membrane repair

Stine Lauritzen Sønder,Marja Jäättelä,Jyoti K Jaiswal,Adam Cohen Simonsen,Theresa Louise Boye,Jörn Dengjel,Kenji Maeda,Jesper Nylandsted,Regine Tölle

doi:10.1038/s41598-019-43143-4

Abstract

The plasma membrane of eukaryotic cells forms the essential barrier to the extracellular environment, and thus plasma membrane disruptions pose a fatal threat to cells. Here, using invasive breast cancer cells we show that the Ca2+ - and phospholipid-binding protein annexin A7 is part of the plasma membrane repair response by enabling assembly of the endosomal sorting complex required for transport (ESCRT) III. Following injury to the plasma membrane and Ca2+ flux into the cytoplasm, annexin A7 forms a complex with apoptosis linked gene-2 (ALG-2) to facilitate proper recruitment and binding of ALG-2 and ALG-2-interacting protein X (ALIX) to the damaged membrane. ALG-2 and ALIX assemble the ESCRT III complex, which helps excise and shed the damaged portion of the plasma membrane during wound healing. Our results reveal a novel function of annexin A7 – enabling plasma membrane repair by regulating ESCRT III-mediated shedding of injured plasma membrane.

Highlights

Members of the annexin (ANXA) protein family are Ca2+-sensitive proteins that regulate various endomembrane processes including vesicle fusion, segregation, and compartmentalization and are implicated in plasma membrane repair mechanisms[5,10]
We show that both ANXA5 and Annexin A7 (ANXA7) are required for repair in breast cancer cells in addition to our previous results implicating ANXA4, ANXA6 and ANXA213, indicating that a network of annexins are participating in the plasma membrane repair response
In the light of our previous findings, showing specific roles of individual annexin family members in repair including induction of membrane curvature triggered by ANXA4 and ANXA627, and regulation of actin accumulation by ANXA2/S100A1113 we hypothesized that ANXA7 plays a distinct function in plasma membrane repair

Summary

Introduction

Members of the annexin (ANXA) protein family are Ca2+-sensitive proteins that regulate various endomembrane processes including vesicle fusion, segregation, and compartmentalization and are implicated in plasma membrane repair mechanisms[5,10]. We found that upon plasma membrane damage triggered by digitonin, nine annexin family members translocate to the damaged plasma membrane of breast cancer cells We show that both ANXA5 and ANXA7 are required for repair in breast cancer cells in addition to our previous results implicating ANXA4, ANXA6 and ANXA213, indicating that a network of annexins are participating in the plasma membrane repair response. In the light of our previous findings, showing specific roles of individual annexin family members in repair including induction of membrane curvature triggered by ANXA4 and ANXA627, and regulation of actin accumulation by ANXA2/S100A1113 we hypothesized that ANXA7 plays a distinct function in plasma membrane repair. Our results show that by enabling Ca2+-triggered ALG-2 and ALIX recruitment at the injured plasma membrane, ANXA7 initiates the process of ESCRT III buildup at the site of injury, which is needed to shed damaged membrane during the repair process

Methods

Results

Conclusion