Immune system: discovered a new regulatory mechanism in diseases such as leukemia


The research "An isoform of the giant protein titin is a master regulator of human T lymphocyte trafficking", published in the journal Cell Reports, concerns the central role of titin, the largest protein encoded by the human genome, in the control of leukocyte trafficking. Titin, also called connectin, is a protein encoded in humans by the TTN gene, and is important in the contraction of striated muscles. This protein functions as a molecular spring, composed of individually folded protein domains, which unwind when the protein is under tension, but reassemble when tension is removed. This Research has highlighted that the mechanical function of titin plays a role in lymphocyte resilience to passive deformation and mechanical stress

The study was carried out thanks to the involvement of various departments of the University of Verona with the help of the department of Molecular and Translational Medicine of the University of Brescia, of the Centro of computational biomedicine of the University of Verona, of the University of Münster in Göttingen, Germany, and of the Institute of Biomedical Technologies of the Cnr of Milan, which played a decisive role in the project.

“This study is the result of more than a decade of research. Many technologies and methodological approaches were developed specifically for this study, which also benefited greatly from a multidisciplinary approach thanks to the contribution of many scientists, each a specialist in a research field", explained Carlo Laudanna, professor of pathology of the department of medicine from the University of Verona. "This work demonstrated the ability of proteomics analysis to obtain important discoveries in the biomedical field," said Pierluigi Mauri, head of the proteomics laboratory and co-founder of the Prometeo Cnr network.
The research work coordinated by Laudanna, and based on an observation from Mauri's laboratory, discovered that human lymphocytes express five new isoforms of titin (three specific for T lymphocytes and two for B lymphocytes). The group demonstrated that the LTTN1 isoform, specifically expressed in T lymphocytes, controls all phases of leukocyte trafficking. Furthermore, LTTN1 regulates the viscoelastic stiffness of T lymphocytes and, in doing so, ensures their survival in the bloodstream as it makes the cells resistant to the continuous deformation and intense mechanical stress that occur in the capillaries during the recirculation.

In the absence of LTTN1, circulating T lymphocytes are, in effect, destroyed. The study demonstrates that LTTN1 is a general molecular regulator of T-lymphocyte mechano-transduction and viscoelastic stiffness, simultaneously addressing many long-debated questions in the field regarding plasma membrane tubulation, morphogenesis, and microvillous architecture. the integration of signal transduction systems and resilience to passive mechanical strain, which is in turn critical for the survival of circulating lymphocytes.

Per informazioni:
Pierluigi Mauri
Cnr - Itb