RATIONALE: The actin cytoskeleton has been implicated in the processing of atherogenic lipoproteins in macrophages. However, the functional role of actin and the regulatory proteins involved are unknown. OBJECTIVE: Coronin-1A (Coro1A) was identified as a differentially expressed transcript in wild-type versus Niemann-Pick type C1 deficient macrophages exposed to acetylated low-density lipoproteins (AcLDL). We investigated whether Coro1A plays a role in the uptake or processing of modified lipoproteins in macrophages and if this is related to its actin regulatory functions. METHODS AND RESULTS: In wild-type primary macrophages, filamentous actin transiently decorated AcLDL containing endosomes that also recruited Coro1A. This dynamic association of F-actin with endosomes was disturbed in Coro1A deficient macrophages. In Coro1A knockout macrophages the uptake of AcLDL was increased, rate of AcLDL delivery to lysosomes enhanced, and lipoprotein-derived cholesteryl ester hydrolysis accelerated. Overexpression of wild-type Coro1A normalized AcLDL uptake in Coro1A knockout macrophages while a Coro1A actin binding mutant did not. Furthermore, the effects of macrophage Coro1A silencing on endosomal actin association and AcLDL delivery to lysosomes resembled those of cofilin silencing. CONCLUSIONS: Coro1A controls actin association with endocytic organelles, thereby negatively regulating endo-lysosomal delivery, degradation of modified lipoproteins and cholesterol deposition in macrophages.
RATIONALE: The actin cytoskeleton has been implicated in the processing of atherogenic lipoproteins in macrophages. However, the functional role of actin and the regulatory proteins involved are unknown. OBJECTIVE:Coronin-1A (Coro1A) was identified as a differentially expressed transcript in wild-type versus Niemann-Pick type C1 deficient macrophages exposed to acetylated low-density lipoproteins (AcLDL). We investigated whether Coro1A plays a role in the uptake or processing of modified lipoproteins in macrophages and if this is related to its actin regulatory functions. METHODS AND RESULTS: In wild-type primary macrophages, filamentous actin transiently decorated AcLDL containing endosomes that also recruited Coro1A. This dynamic association of F-actin with endosomes was disturbed in Coro1A deficient macrophages. In Coro1A knockout macrophages the uptake of AcLDL was increased, rate of AcLDL delivery to lysosomes enhanced, and lipoprotein-derived cholesteryl ester hydrolysis accelerated. Overexpression of wild-type Coro1A normalized AcLDL uptake in Coro1A knockout macrophages while a Coro1A actin binding mutant did not. Furthermore, the effects of macrophage Coro1A silencing on endosomal actin association and AcLDL delivery to lysosomes resembled those of cofilin silencing. CONCLUSIONS:Coro1A controls actin association with endocytic organelles, thereby negatively regulating endo-lysosomal delivery, degradation of modified lipoproteins and cholesterol deposition in macrophages.
Authors: Alessia Castagnino; Antonio Castro-Castro; Marie Irondelle; Alan Guichard; Catalina Lodillinsky; Laetitia Fuhrmann; Sophie Vacher; Sonia Agüera-González; Anna Zagryazhskaya-Masson; Maryse Romao; Carole El Kesrouani; Angelika A Noegel; Thierry Dubois; Graça Raposo; James E Bear; Christoph S Clemen; Anne Vincent-Salomon; Ivan Bièche; Philippe Chavrier Journal: Oncogene Date: 2018-07-31 Impact factor: 9.867
Authors: Panu K Luukkonen; Auli Nick; Maarit Hölttä-Vuori; Christoph Thiele; Elina Isokuortti; Susanna Lallukka-Brück; You Zhou; Antti Hakkarainen; Nina Lundbom; Markku Peltonen; Marju Orho-Melander; Matej Orešič; Tuulia Hyötyläinen; Leanne Hodson; Elina Ikonen; Hannele Yki-Järvinen Journal: JCI Insight Date: 2019-08-22
Authors: Sanjeev Sinha; Gaurav Gupta; Sagnik Biswas; Kartik Gupta; P P Singh; Rahul Jain; S K Sharma; Bimal K Das Journal: Indian J Med Res Date: 2021-06 Impact factor: 5.274