Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis.
Chorea-acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder and cognitive and behavioral abnormalities as well as acanthocytosis. The disease is caused by loss-of-function mutations of the gene encoding vacuolar protein sorting-associated protein 13A (VPS13A) or chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea-acanthocytosis remains enigmatic. Here we show decreased phosphoinositide-3-kinase (PI3K)-p85-subunit phosphorylation, ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and p21 protein-activated kinase 1 (PAK1) phosphorylation as well as depolymerized cortical actin in erythrocytes from patients with chorea-acanthocytosis and in K562-erythrocytic cells following chorein silencing. Pharmacological inhibition of PI3K, Rac1, or PAK1 similarly triggered actin depolymerization. Moreover, in K562 cells, both chorein silencing and PAK1 inhibition with IPA-3 decreased phosphorylation of Bad, a Bcl2-associated protein, promoting apoptosis by forming mitochondrial pores, followed by mitochondrial depolarization, DNA fragmentation, and phosphatidylserine exposure at the cell surface, all hallmarks of apoptosis. Our observations reveal chorein as a novel powerful regulator of cytoskeletal architecture and cell survival, thus explaining erythrocyte misshape and possibly neurodegeneration in chorea-acanthocytosis.
Department of Physiology, Universität Tübingen, Tübingen, Germany.
Michael
M
Föller
Andreas
A
Hermann
Shuchen
S
Gu
Ioana
I
Alesutan
Syed M
SM
Qadri
Oliver
O
Borst
Eva-Maria
EM
Schmidt
Franziska
F
Schiele
Jennifer Müller
JM
vom Hagen
Carsten
C
Saft
Ludger
L
Schöls
Holger
H
Lerche
Christos
C
Stournaras
Alexander
A
Storch
Florian
F
Lang
D000050:Acanthocytes / Q000166:cytology / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054546:Neuroacanthocytosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000199:Actins; C429654:VPS13A protein, human; D033921:Vesicular Transport Proteins; D051025:bcl-Associated Death Protein; D019869:Phosphatidylinositol 3-Kinases; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein