Integrin α4β1 mediates a mixture of rolling and firm cell adhesion on vascular cell adhesion molecule-1 (VCAM-1) substrates when in the resting state, while only supports firm cell adhesion upon activation, playing an important role in leukocyte trafficking and immune homeostasis. Intensive studies have revealed that kindlin-3 functions as a coactivator of leukocyte integrins by binding to integrin β tails and triggering integrin activation via inside-out signaling. However, the role of kindlin-3 in regulating the resting α4β1-mediated cell adhesion is not well characterized.
Led by Professor CHEN Jianfeng from the Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Dr. LU Ling and their colleagues discovered that kindlin-3 was required for the resting α4β1-mediated firm cell adhesion but not rolling adhesion. Knockdown of kindlin-3 significantly decreased the binding of kindlin-3 to β1 and down-regulated the binding affinity of the resting α4β1 to soluble VCAM-1. Notably, it converted the resting α4β1-mediated firm cell adhesion to rolling adhesion on VCAM-1 substrates, increased cell rolling velocity and impaired the stability of cell adhesion. By contrast, firm cell adhesion mediated by Mn2+-activated α4β1 was barely affected by knockdown of kindlin-3. Structurally, lack of kindlin-3 led to a more bent conformation of the resting α4β1. Thus kindlin-3 plays an important role in maintaining a proper conformation of the resting α4β1 to mediate both rolling and firm cell adhesion. Defective kindlin-3 binding to the resting α4β1 leads to a transition from firm to rolling cell adhesion on VCAM-1, implying its potential role in regulating the transition between integrin mediated rolling and firm cell adhesion. Clinically, loss of kindlin-3 expression accounts for the pathogenesis of LAD (leukocyte adhesion deficiency) type III that is characterized by bleeding disorders and defective recruitment of leukocytes into sites of infection. This study suggests that leukocytes in these patients might have several functional deficiencies of integrin α4β1, including lack of firm cell adhesion mediated by the resting α4β1, less stable α4β1-VCAM-1 interactions and higher rolling velocity besides the deficient activation of integrin via inside-out signaling. These findings shed a new light on the understanding and management of the disease.
This work entitled “Kindlin-3 is essential for resting integrin α4β1- mediated firm cell adhesion under shear flow conditions” was published online in The Journal of Biological Chemistry on March 18, 2016. It is funded by grants from the National Basic Research Program of China, National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality. This work was also technically supported by the SIBCB Cell Biology Core Facility and Molecular Biology Core Facility.
CONTACT:
JianFeng Chen. Ph.D. Professor
Institute of Biochemistry and Cell Biology
Shanghai Institutes for Biological Sciences
Chinese Academy of Sciences
Biochemistry and Cell Biology Building, Rm 411
320 YueYang Road, Shanghai 200031, China
Tel: 86-21-54921142 Fax: 86-21-54921658
Email: jfchen@sibs.ac.cn
Link to the article: http://www.jbc.org/content/early/2016/03/18/jbc.M116.717694.abstract
Appendix：
