Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering the mechanisms underlying septin-associated pathologies. This article has an associated First Person interview with the first author of the paper.

Cell Engineering Corporation 532 0011 Osaka Japan

Centre de Recherche en Cancérologie de Marseille INSERM Institut Paoli Calmettes Aix Marseille Univ CNRS 13009 Marseille France

Department of Bioengineering Graduate School of Engineering Osaka City University 558 8585 Osaka Japan

Department of Bionanoscience Kavli Institute of Nanoscience Delft Delft University of Technology 2629 HZ Delft The Netherlands

Department of Pathological Physiology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Institut Fresnel CNRS UMR7249 Aix Marseille Univ Centrale Marseille 13013 Marseille France

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