Giada Vanni,Anna Citron,Ambela Suli,Paolo Contessotto,Robin Caire,Alessandro Gandin,Giovanna Mantovan,Francesca Zanconato,Giovanna Brusatin,Michele Di Palma,Elisa Peirano,Lisa Sofia Pozzer,Carlo Albanese,Roberto A Steiner,Michelangelo Cordenonsi,Tito Panciera,Stefano Piccolo
{"title":"Microtubule architecture connects AMOT stability to YAP/TAZ mechanotransduction and Hippo signalling.","authors":"Giada Vanni,Anna Citron,Ambela Suli,Paolo Contessotto,Robin Caire,Alessandro Gandin,Giovanna Mantovan,Francesca Zanconato,Giovanna Brusatin,Michele Di Palma,Elisa Peirano,Lisa Sofia Pozzer,Carlo Albanese,Roberto A Steiner,Michelangelo Cordenonsi,Tito Panciera,Stefano Piccolo","doi":"10.1038/s41556-025-01773-z","DOIUrl":null,"url":null,"abstract":"Cellular mechanotransduction is a key informational system, yet its mechanisms remain elusive. Here we unveil the role of microtubules in mechanosignalling, operating downstream of subnuclear F-actin and nuclear envelope mechanics. Upon mechanical activation, microtubules reorganize from a perinuclear cage into a radial array nucleated by centrosomes. This structural rearrangement triggers degradation of AMOT proteins, which we identify as key mechanical rheostats that sequester YAP/TAZ in the cytoplasm. AMOT is stable in mechano-OFF but degraded in mechano-ON cell states, where microtubules allow AMOT rapid transport to the pericentrosomal proteasome in complex with dynein/dynactin. This process ensures swift control of YAP/TAZ function in response to changes in cell mechanics, with experimental loss of AMOT proteins rendering cells insensitive to mechanical modulations. Ras/RTK oncogenes promote YAP/TAZ-dependent tumorigenesis by corrupting this AMOT-centred mechanical checkpoint. Notably, the Hippo pathway fine-tunes mechanotransduction: LATS kinases phosphorylate AMOT, shielding it from degradation, thereby indirectly restraining YAP/TAZ. Thus, AMOT protein stability serves as a hub linking cytoskeletal reorganization and Hippo signalling to YAP/TAZ mechanosignalling.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"99 1","pages":""},"PeriodicalIF":19.1000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41556-025-01773-z","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cellular mechanotransduction is a key informational system, yet its mechanisms remain elusive. Here we unveil the role of microtubules in mechanosignalling, operating downstream of subnuclear F-actin and nuclear envelope mechanics. Upon mechanical activation, microtubules reorganize from a perinuclear cage into a radial array nucleated by centrosomes. This structural rearrangement triggers degradation of AMOT proteins, which we identify as key mechanical rheostats that sequester YAP/TAZ in the cytoplasm. AMOT is stable in mechano-OFF but degraded in mechano-ON cell states, where microtubules allow AMOT rapid transport to the pericentrosomal proteasome in complex with dynein/dynactin. This process ensures swift control of YAP/TAZ function in response to changes in cell mechanics, with experimental loss of AMOT proteins rendering cells insensitive to mechanical modulations. Ras/RTK oncogenes promote YAP/TAZ-dependent tumorigenesis by corrupting this AMOT-centred mechanical checkpoint. Notably, the Hippo pathway fine-tunes mechanotransduction: LATS kinases phosphorylate AMOT, shielding it from degradation, thereby indirectly restraining YAP/TAZ. Thus, AMOT protein stability serves as a hub linking cytoskeletal reorganization and Hippo signalling to YAP/TAZ mechanosignalling.
期刊介绍:
Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to:
-Autophagy
-Cancer biology
-Cell adhesion and migration
-Cell cycle and growth
-Cell death
-Chromatin and epigenetics
-Cytoskeletal dynamics
-Developmental biology
-DNA replication and repair
-Mechanisms of human disease
-Mechanobiology
-Membrane traffic and dynamics
-Metabolism
-Nuclear organization and dynamics
-Organelle biology
-Proteolysis and quality control
-RNA biology
-Signal transduction
-Stem cell biology