Akt and CHIP coregulate tau degradation through coordinated interactions.
A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.
Dickey
Chad A
CA
Department of Molecular Pharmacology and Physiology and H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA. cdickey1@health.usf.edu
Koren
John
J
Zhang
Yong-Jie
YJ
Xu
Ya-Fei
YF
Jinwal
Umesh K
UK
Birnbaum
Morris J
MJ
Monks
Bobby
B
Sun
Mei
M
Cheng
Jin Q
JQ
Patterson
Cam
C
Bailey
Rachel M
RM
Dunmore
Judith
J
Soresh
Sareh
S
Leon
Carlos
C
Morgan
Dave
D
Petrucelli
Leonard
L
D000544:Alzheimer Disease; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D016875:tau Proteins; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C122043:Mark2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt