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BackgroundIntegrins are required for normal muscle differentiation and disruptions in integrin signaling result in human muscle disease. The intracellular components that regulate integrin function during myogenesis are poorly understood. Unc-112 is an integrin-associated protein required for muscle development in C. elegans. To better understand the intracellular effectors of integrin signaling in muscle, we examined the mammalian homolog of Unc-112, kindlin-2.ResultsKindlin-2 expression is upregulated during differentiation and highly enriched at sites of integrin localization. RNAi knockdown of kindlin-2 in C2C12 cells results in significant abnormalities during the early stages of myogenesis. Specifically, differentiating myocytes lacking kindlin-2 are unable to elongate and fail to fuse into multinucleated myotubes. These changes are correlated with decreased cell substratum adhesion and increased cell motility. They are also associated with redistribution of a known kindlin-2 binding partner, integrin linked kinase (ILK), to the membrane insoluble subcellular fraction.ConclusionIn all, our study reveals kindlin-2 as a novel integrin adaptor protein important for muscle differentiation, and identifies it particularly as a critical regulator of myocyte elongation.

cAberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.A irway mucus forms a protective coating that entraps foreign particles and microbes, facilitating their clearance by mucociliary transport. Mucus is composed mainly of mucin glycoproteins, water, ions, and cellular debris. Mucins are the major macromolecular component of the mucus gel responsible for its viscoelastic, rheological, and clearance properties. MUC5AC and MUC5B are the major mucins of human airways (1-3). Although a deficient mucous barrier intuitively leaves the lungs vulnerable to injury, aberrant mucin secretion and accumulation contribute significantly to the pathogenesis of airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) (1-4). Mucus plugging in asthmatic and COPD lungs is a major cause of airway narrowing and death (5, 6). Furthermore, hypersecretion of MUC5AC is detrimental during acute lung injury (7).The ability of microbial pathogens to induce mucus secretion suggests that it is one of the mechanisms of infection-induced exacerbation in airway diseases (8-11). M. pneumoniae is the most common cause of community-acquired pneumonia. Moreover, M. pneumoniae has long been recognized as a trigger of both chronic infection and acute exacerbation in multiple chronic airway diseases, including asthma (12, 13). Several virulence mechanisms of M. pneumoniae are known, including cytoadherence through a polar attachment organelle (14), generation of reactive oxygen species (ROS) (15), and secretion of the community-acquired respiratory distress syndrome (CARDS) toxin (16). Alth...