学术报告：Mechanical force triggers transmembrane signaling by inducing lipid phase separation
邀 请 人：生命科学与技术学院 马聪 教授
All cells are subjected to mechanical force, and force may regulate a variety of cellular and molecular functions. We use T cells as model system to study the impact for mechanical force at molecular or cellular level. T cells rely upon specific recognition between T-cell receptor (TCR) and peptide conjugated major histocompatibility molecule (pMHC) on an antigen-presenting cell to trigger activation signals. The TCR complex is composed of an αβ heterodimer and the non-covalently associated CD3 signaling components (CD3εγ, CD3εδ, CD3ζζ). The juxtaposition of the squat and rigid heterodimeric CD3 structures on short stalks that flank the taller αβ heterodimer, which tethered to the T cell membrane by long linkers, suggested a TCR-based signal transduction mechanism initiated by mechanical triggering upon antigen recognition in the extracellular domains. Moreover, T-cell signals take “two-signal” format. Besides the signals mediated by the TCR/pMHC interactions, both stimulatory and inhibitory secondary signals exist. These costimulatory and coinhibitory pathways have broader biological functions. The molecules involved in the costimulatory pathways include CD28 and ICOS. CTLA-4 and PD-1 involved in the coinhibitory pathways. Molecular architecture (long extracellular stalk) indicated that PD-1 signal transduction should also be force dependent. Our studies suggest possible molecular mechanism on TCR and PD-1 signal transduction, where mechanical forces trigger the phase separation of membrane lipids, which facilitate the downstream signaling cascade. We proposed that the transmembrane signaling for a class of receptors is mediated by mechanical force, especially the ones with single transmembrane domain and long stalk sequence in the extracellular region. Force may play roles at different levels in activate these receptors for their signal initiation and transmission.