Deciphering the remodeling of actin-membrane interactions by BAR domain proteins
Dr. Laura Picas
Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS UMR 9004, University of Montpellier, France
The shaping of cellular membranes is essential to support developmental processes and cellular functions. Several cellular processes emerge from curvature generation and display a wide heterogeneity of shapes, such as endo- and exocytosis, T-tubule formation in muscular cells, or actin-driven structures during migration, axonal guidance, zippering of epithelial sheets, or myoblast fusion. Curvature generation relies on the dynamic action of protein complexes, and at the plasma membrane, this process is regulated by the coupling between the cell membrane and the actin cytoskeleton.
Bin/Amphiphysin/Rvs (BAR) domain proteins are among the most studied protein families in curvature generation. Proteins of this family are characterized by a modular architecture and an intrinsically curved membrane-binding BAR domain that can vary from a curvature crescent-shaped N-BAR, a less curved F-BAR, to an inverse curvature I-BAR. The BAR domain is often followed by Rho GTPase signaling domains and/or auxiliary domains mediating protein-protein interactions, such as the SH3 domain, which binds cytoskeletal assembly factors and the dynamin GTPase.
We could previously show that the N-BAR domain protein BIN1, which is implicated in T-tubule biogenesis and participate in endocytosis in specific cell types, locally increases the density of the plasma membrane phosphoinositide PI(4,5)P2 to facilitate dynamin recruitment.
In this seminar, I will present our recent work showing that BIN1 can also interact with and bundle F-actin. Through this new function, we found that BIN1 expression is necessary and sufficient to induce filopodia formation in myoblasts. We also identify new BIN1-binding partners, including IRSp53 and ezrin, during filopodia formation. Finally, we demonstrate that BIN1 regulates the membrane-to-cortex mechanics and is required to recruit active phosphorylated ezrin at filopodia. Thus, BIN1 constitutes a functional membrane and actin-remodeling scaffold capable of orchestrating antagonistic membrane topologies at the cell cortex.
Selected references
- El Alaoui F, Casuso I, Sanchez-Fuentes D, Arpin-Andre C, Rathar R, Baecker V, Castro A, Lorca T, Viaud J, Vassilopoulos S, Carretero-Genevrier A, Picas L. Structural organization and dynamics of FCHo2 docking on membranes. eLife 2022
- Sansen T, Sanchez-Fuentes D, Rathar R, Colom-Diego A, El Alaoui F, Viaud J, Macchione M, de Rossi S, Matile S, Gaudin R, Bäcker V, Carretero-Genevrier A, Picas L. Mapping Cell Membrane Organization and Dynamics Using Soft Nanoimprint Lithography. ACS Appl Mater Interfaces. 2020
- Tsai FC, Bertin A, Bousquet H, Manzi J, Senju Y, Tsai MC, Picas L, Miserey-Lenkei S, Lappalainen P, Lemichez E, Coudrier E, Bassereau P. Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner. eLife 2018
- Picas L, Gaits-Iacovoni F, Goud B. The emerging role of phosphoinositide clustering in intracellular trafficking and signal transduction. F1000Research 2016
- Picas L, Viaud J, Schauer K, Vanni S, Hni K, Fraisier V, Roux A, Bassereau P, Gaits-Iacovoni F, Payrastre B, Laporte J, Manneville J-B, Goud B. BIN1/M-Amphiphysin2 induces clustering of phosphoinositides to recruit its downstream partner dynamin. Nat Commun 2014
Osteoclast, the forgotten multinucleated innate immune cell
Dr. Claudine Blin
Laboratoire de PhysioMédecine Moléculaire (LP2M), CNRS UMR7370, University of Nice, France
Osteoclasts are multinucleated cells of myeloid origin, well described for their essential role in bone remodeling and bone resorption. However, beyond bone resorption and like other monocytic cells, osteoclasts are true innate immune cells participating in immune responses, a function that has long been neglected.
Osteoclasts share the same properties as mononuclear phagocytes (macrophages, dendritic cells and monocytes). Over the past decade, osteoclasts have been characterized as antigen-presenting cells driving T cell responses towards tolerance or inflammation. They also have immunomodulatory capacity. Finally, these different functions are correlated with a diversity in osteoclasts subpopulations that remains largely unexplored.
Using transcriptomic approaches and functional assays, our results revealed the existence of different subsets of osteoclasts with distinct immune and bone resorption capacities. We have also shown that these capacities and diversity depend on the cellular origin of the osteoclasts. Finally, based on the specific characteristics of osteoclasts associated with pathological bone destruction, we demonstrated that specifically targeting the emergence of these osteoclasts reduces bone destruction in osteoporotic mice without affecting physiological bone remodeling.
These data open up new therapeutic perspectives for bone destruction and deepen our understanding of osteoclasts by reconsidering them in their context as innate immune cells.
Selected references
- Madel MB, Halper J, Ibáñez L, Claire L, Rouleau M, Boutin A, Mahler A, Pontier-Bres R, Ciucci T, Topi M, Hue C, Amiaud J, Iborra S, Sancho D, Heymann D, Garchon HJ, Czerucka D, Apparailly F, Duroux-Richard I, Wakkach A, Blin-Wakkach C. eLife 2023
- Madel MB, Ibáñez L, Ciucci T, Halper J, Rouleau M, Boutin A, Hue C, Duroux-Richard I, Apparailly F, Garchon HJ, Wakkach A, Blin-Wakkach C. eLife 2020
- Madel MB, Ibáñez L, Rouleau M, Wakkach A, Blin-Wakkach C. Front Immunol 2018
- Ibáñez L, Abou-Ezzi G, Ciucci T, Amiot V, Belaïd N, Obino D, Mansour A, Rouleau M, Wakkach A, Blin-Wakkach C. J Bone Miner Res 2016