Endosomal actin remodeling by coronin-1A controls lipoprotein uptake and degradation in macrophages.
BACKGROUND
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.


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.
Institute of Biomedicine/Anatomy, University of Helsinki, Finland.
Maarit
M
Hölttä-Vuori
Saara
S
Vainio
Maria
M
Kauppi
Miranda
M
Van Eck
Eija
E
Jokitalo
Elina
E
Ikonen
D000199:Actins / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D015388:Organelles / Q000378:metabolism; D059748:Proteolysis
D000199:Actins; D008074:Lipoproteins; D008840:Microfilament Proteins; C072061:coronin proteins; D002784:Cholesterol