An isoform of the giant protein titin is a master regulator of human T lymphocyte trafficking
Lara Toffali,
Beatrice D’Ulivo,
Cinzia Giagulli,
Alessio Montresor,
Elena Zenaro,
Massimo Delledonne,
Marzia Rossato,
Barbara Iadarola,
Andrea Sbarbati,
Paolo Bernardi,
Gabriele Angelini,
Barbara Rossi,
Nicola Lopez,
Wolfgang A. Linke,
Andreas Unger,
Dario Di Silvestre,
Louise Benazzi,
Antonella De Palma,
Sara Motta,
Gabriela Constantin,
Pierluigi Mauri,
Carlo Laudanna
Affiliations
Lara Toffali
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy
Beatrice D’Ulivo
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy
Cinzia Giagulli
Department of Molecular and Translational Medicine, University of Brescia; 25123 Brescia, Lombardia, Italy
Alessio Montresor
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy; The Center for Biomedical Computing (CBMC), University of Verona; 37134 Verona, Veneto, Italy
Elena Zenaro
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy
Massimo Delledonne
Department of Biotechnology, University of Verona; 37134 Verona, Veneto, Italy
Marzia Rossato
Department of Biotechnology, University of Verona; 37134 Verona, Veneto, Italy
Barbara Iadarola
Department of Biotechnology, University of Verona; 37134 Verona, Veneto, Italy
Andrea Sbarbati
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; 37134 Verona, Veneto, Italy
Paolo Bernardi
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; 37134 Verona, Veneto, Italy
Gabriele Angelini
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy
Barbara Rossi
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy
Nicola Lopez
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy
Wolfgang A. Linke
Institute of Physiology II, University of Muenster, and Heart Center, University Medicine; 37075 Göttingen, Germany
Andreas Unger
Institute of Physiology II, University of Muenster, and Heart Center, University Medicine; 37075 Göttingen, Germany
Dario Di Silvestre
Institute of Biomedical Technologies (ITB) CNR; 20090 Milan, Lombardia, Italy
Louise Benazzi
Institute of Biomedical Technologies (ITB) CNR; 20090 Milan, Lombardia, Italy
Antonella De Palma
Institute of Biomedical Technologies (ITB) CNR; 20090 Milan, Lombardia, Italy
Sara Motta
Institute of Biomedical Technologies (ITB) CNR; 20090 Milan, Lombardia, Italy
Gabriela Constantin
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy; The Center for Biomedical Computing (CBMC), University of Verona; 37134 Verona, Veneto, Italy
Pierluigi Mauri
Institute of Biomedical Technologies (ITB) CNR; 20090 Milan, Lombardia, Italy
Carlo Laudanna
Department of Medicine, Division of General Pathology, Laboratory of Cell Trafficking and Signal Transduction, University of Verona; 37134 Verona, Veneto, Italy; The Center for Biomedical Computing (CBMC), University of Verona; 37134 Verona, Veneto, Italy; Corresponding author
Summary: Response to multiple microenvironmental cues and resilience to mechanical stress are essential features of trafficking leukocytes. Here, we describe unexpected role of titin (TTN), the largest protein encoded by the human genome, in the regulation of mechanisms of lymphocyte trafficking. Human T and B lymphocytes express five TTN isoforms, exhibiting cell-specific expression, distinct localization to plasma membrane microdomains, and different distribution to cytosolic versus nuclear compartments. In T lymphocytes, the LTTN1 isoform governs the morphogenesis of plasma membrane microvilli independently of ERM protein phosphorylation status, thus allowing selectin-mediated capturing and rolling adhesions. Likewise, LTTN1 controls chemokine-triggered integrin activation. Accordingly, LTTN1 mediates rho and rap small GTPases activation, but not actin polymerization. In contrast, chemotaxis is facilitated by LTTN1 degradation. Finally, LTTN1 controls resilience to passive cell deformation and ensures T lymphocyte survival in the blood stream. LTTN1 is, thus, a critical and versatile housekeeping regulator of T lymphocyte trafficking.
