02166nas a2200349 4500000000100000008004100001260003600042653003300078653002200111653001200133653001500145653003700160100001500197700001700212700001500229700001500244700001200259700001100271700001600282700001300298700001300311700001600324700002100340700001000361700001200371700001500383700001500398245012400413856006100537520119300598022002501791 2023 d bAmerican Chemical Society (ACS)10aGeneral Chemical Engineering10aGeneral Chemistry10aPGL-III10atratamento10aPhenolic Glycolipid Biosynthesis1 aIshizuka S1 avan Dijk JHM1 aKawakita T1 aMiyamoto Y1 aMaeda Y1 aGoto M1 aLe Calvez G1 aGroot LM1 aWitte MD1 aMinnaard AJ1 avan der Marel GA1 aAto M1 aNagae M1 aCodée JDC1 aYamasaki S00aPGL-III, a Rare Intermediate of Mycobacterium leprae Phenolic Glycolipid Biosynthesis, Is a Potent Mincle Ligand uhttps://pubs.acs.org/doi/epdf/10.1021/acscentsci.3c000403 a

Although leprosy (Hansen’s disease) is one of the oldest known diseases, the pathogenicity of Mycobacterium leprae (M. leprae) remains enigmatic. Indeed, the cell wall components responsible for the immune response against M. leprae are as yet largely unidentified. We reveal here phenolic glycolipid-III (PGL-III) as an M. leprae-specific ligand for the immune receptor Mincle. PGL-III is a scarcely present trisaccharide intermediate in the biosynthetic pathway to PGL-I, an abundant and characteristic M. leprae glycolipid. Using activity-based purification, we identified PGL-III as a Mincle ligand that is more potent than the well-known M. tuberculosis trehalose dimycolate. The cocrystal structure of Mincle and a synthetic PGL-III analogue revealed a unique recognition mode, implying that it can engage multiple Mincle molecules. In Mincle-deficient mice infected with M. leprae, increased bacterial burden with gross pathologies were observed. These results show that PGL-III is a noncanonical ligand recognized by Mincle, triggering protective immunity.

 a2374-7943, 2374-7951