An isoform of the giant protein titin is a master regulator of human T lymphocyte trafficking

• Published in: Cell reports (Cambridge) Vol. 42; no. 5; p. 112516
• Main Authors: Toffali, Lara, D’Ulivo, Beatrice, Giagulli, Cinzia, Montresor, Alessio, Zenaro, Elena, Delledonne, Massimo, Rossato, Marzia, Iadarola, Barbara, Sbarbati, Andrea, Bernardi, Paolo, Angelini, Gabriele, Rossi, Barbara, Lopez, Nicola, Linke, Wolfgang A., Unger, Andreas, Di Silvestre, Dario, Benazzi, Louise, De Palma, Antonella, Motta, Sara, Constantin, Gabriela, Mauri, Pierluigi, Laudanna, Carlo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-05-2023; Elsevier
• Subjects: adhesion; Cell Adhesion - physiology; cell deformability; chemokine; Connectin - metabolism; CP: Immunology; Humans; integrin activation; leukocyte trafficking; Lymphocyte Activation; microvilli; migration; Protein Isoforms - metabolism; selectin; Signal Transduction; T-Lymphocytes; titin; titin; CP: Immunology; chemokine; selectin; signal transduction; integrin activation; leukocyte trafficking; migration; microvilli; adhesion; cell deformability
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112516

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.
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•Human T and B lymphocytes express five isoforms of the giant protein TTN•In T lymphocytes, the LTTN1 isoform regulates the structure of microvilli•LTTN1 regulates integrin activation and chemotaxis•LTTN1 controls cell stiffness and deformability and ensures survival in the circulation
Toffali et al. find that human lymphocytes express five isoforms of TTN. In T lymphocytes, the LTTN1 isoform regulates microvilli structure, integrin activation, and chemotaxis. Moreover, LTTN1 controls cell stiffness and resilience to deformation and ensures survival in the blood stream. LTTN1 is, thus, a central regulator of lymphocyte trafficking.