RESUMEN
Lipids are prominent components of the mycobacterial cell wall, and they play critical roles not only in maintaining biofilm formation but also in resisting environmental stress, including drug resistance. However, information regarding the mechanism mediating mycobacterial lipid synthesis remains limited. PatA is a membrane-associated acyltransferase and synthesizes phosphatidyl-myo-inositol mannosides (PIMs) in mycobacteria. Here, we found that PatA could regulate the synthesis of lipids (except mycolic acids) to maintain biofilm formation and environmental stress resistance in Mycolicibacterium smegmatis. Interestingly, the deletion of patA significantly enhanced isoniazid (INH) resistance in M. smegmatis, although it reduced bacterial biofilm formation. This might be due to the fact that the patA deletion promoted the synthesis of mycolic acids through an unknown synthesis pathway other than the reported fatty acid synthase (FAS) pathway, which could effectively counteract the inhibition by INH of mycolic acid synthesis in mycobacteria. Furthermore, the amino acid sequences and physiological functions of PatA were highly conserved in mycobacteria. Therefore, we found a mycolic acid synthesis pathway regulated by PatA in mycobacteria. In addition, PatA also affected biofilm formation and environmental stress resistance by regulating the synthesis of lipids (except mycolic acids) in mycobacteria. IMPORTANCE Tuberculosis, caused by Mycobacterium tuberculosis, leads to a large number of human deaths every year. This is so serious, which is due mainly to the drug resistance of mycobacteria. INH kills M. tuberculosis by inhibiting the synthesis of mycolic acids, which are synthesized by the FAS pathway. However, whether there is another mycolic acid synthesis pathway is unknown. In this study, we found a PatA-mediated mycolic acid synthesis pathway that led to INH resistance of in patA-deleted mutant. In addition, we first report the regulatory effect of PatA on mycobacterial biofilm formation, which could affect the bacterial response to environmental stress. Our findings represent a new model for regulating biofilm formation by mycobacteria. More importantly, the discovery of the PatA-mediated mycolic acid synthesis pathway indicates that the study of mycobacterial lipids has entered a new stage, and the enzymes might be new targets of antituberculosis drugs.
Asunto(s)
Mycobacterium tuberculosis , Ácidos Micólicos , Humanos , Ácidos Micólicos/metabolismo , Ácidos Micólicos/farmacología , Isoniazida/farmacología , Mycobacterium smegmatis/metabolismo , Biopelículas , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismoRESUMEN
D-xylose is the most abundant fermentable pentose, which usually represents an architectural component of the bacterial cell wall. However, its regulatory function and the involved signaling pathway in bacteria remain largely unclear. Here, we show that D-xylose can act as a signaling molecule to regulate the lipid metabolism and affect multiple physiological characteristics in mycobacteria. D-xylose directly interacts with XylR and inhibits its DNA-binding ability, thus blocking XylR-mediated repression. The xylose inhibitor, XylR, plays a global regulatory role and affects the expression of 166 mycobacterial genes that are involved in lipid synthesis and metabolism. Furthermore, we show that the xylose-dependent gene regulation of XylR affects the multiple physiological characteristics of Mycobacterium smegmatis, including bacterial size, colony phenotype, biofilm formation, cell aggregation, and antibiotic resistance. Finally, we found that XylR inhibited the survival of Mycobacterium bovis BCG in the host. Our findings provide novel insights into the molecular mechanism of lipid metabolism regulation and its correlation with bacterial physiological phenotypes.
Asunto(s)
Factores de Transcripción , Xilosa , Xilosa/metabolismo , Factores de Transcripción/metabolismo , Metabolismo de los Lípidos , Pentosas , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/metabolismo , Regulación Bacteriana de la Expresión Génica , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismoRESUMEN
Mesenchymal stem cells (MSCs) are multipotent stem cells. In addition to the capacity for self-renewal and multipotential differentiation, MSCs also have the following characteristics. MSCs can exert immunomodulatory functions through interaction with innate or adaptive immune cells, MSCs with poor immunogenicity can be used for allogeneic transplantation, and MSCs can "home" to inflammation and tumour sites. Based on these biological properties, MSCs demonstrate broad clinical application prospects in the treatment of tissue injury, autoimmune diseases, transplantation, cancer and other inflammation-related diseases. In this review we describe the biological characteristics of MSCs and discuss the research advances of MSCs in regenerative medicine, immunomodulation, oncology, and COVID-19, to fully understand the range of diseases in which MSC therapy may be beneficial.