Abstract
The role of Gαi proteins coupled to chemokine receptors in directed migration of immune cells is well understood. In this study we show that the separate class of Gαq/11 proteins is required for the underlying ability of T cells to migrate both randomly and in a directed chemokine-dependent manner. Interfering with Gαq or Gα11 using dominant negative cDNA constructs or siRNA for Gαq causes accumulation of LFA-1 adhesions and stalled migration. Gαq/11 has an impact on LFA-1 expression at plasma membrane level and also on its internalization. Additionally Gαq co-localizes with LFA-1- and EEA1-expressing intracellular vesicles and partially with Rap1- but not Rab11-expressing vesicles. However the influence of Gαq is not confined to the vesicles that express it, as its reduction alters intracellular trafficking of other vesicles involved in recycling. In summary vesicle-associated Gαq/11 is required for the turnover of LFA-1 adhesion that is necessary for migration. These G proteins participate directly in the initial phase of recycling and this has an impact on later stages of the endo-exocytic pathway.
Highlights
Small chemoattractant peptides called chemokines direct T lymphocytes (T cells) to arrest on post-capillary venules at sites of infection or injury [1,2]
Transfection of T cells with a dominant negative (DN) cDNA construct of the G protein, Gai2, which is involved in chemokinemediated chemoattraction [13], caused decreased migration towards CXCL12 (8764% decrease) (Fig. 1A)
Unable to respond to the chemokine, T cells transfected with DN Gai2 cDNA had the same capacity as cells expressing the vector control to migrate randomly on surfaces coated with the LFA-1 ligand, intercellular adhesion molecule-1 (ICAM-1) (Fig. 1B)
Summary
Small chemoattractant peptides called chemokines direct T lymphocytes (T cells) to arrest on post-capillary venules at sites of infection or injury [1,2]. Chemokines bind to G protein-coupled receptors (GPCRs), initiating signalling that activates integrins such as lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, aLb2) [3,4]. The chemokine GPCRs are coupled to heterotrimeric G proteins composed of a, b and c subunits and signal through active Gai-GTP and Gbc dimers leading to generation of intracellular effectors such as Ca2+ and diacylglycerol [5,6]. One of the key downstream effectors of chemokine triggered signalling is the GTPase Rap. One of the key downstream effectors of chemokine triggered signalling is the GTPase Rap1 It has several critical roles in LFA-1 activation that lead to arrest of circulating T cells onto vessels and their subsequent firm adhesion to and migration along the vessel walls and into tissue [4,7]. A positive role was demonstrated by the failure both of Ga11-inhibited myeloid leukaemia cells to migrate to lymphoid tissues and of the LFA-1-
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