Akt and CHIP coregulate tau degradation through coordinated interactions

Abstract

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.Alzheimer's disease ͉ cell signaling ͉ chaperone ͉ MARK2/PAR1

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

“…Furthermore, both Tau dimer and the HSP90 client kinase Fyn (19,20) were reduced by curcumin (Fig. 2C) without impacting Ser(P)-262 Tau (not shown), a Tau species unrecognized by the CHIP/HSP90 complex (15).…”

“…HSP90 inhibition typically increases HSP90 and HSP70 levels via feedback to HSF-1 (15). Curcumin elevated HSP90 protein in both cytosolic-and membrane-enriched fractions, which could enhance misfolded Tau clearance by CHIP/ HSP90.…”

Conformational dynamics of the molecular chaperone Hsp90

“…Inhibition of Hsp90 with small molecules such as geldanamycin and its derivatives has been shown to be antitumorigenic, and several of these compounds are currently in clinical trials (Chiosis et al, 2003;Neckers & Ivy, 2003;Solit et al, 2008;Workman, 2004). Hsp90 has also been implicated in other diseases including Alzheimers (Dickey et al, 2008), vascular disease (Shah et al, 1999), and viral diseses (Geller et al, 2007). In the case of RNA viruses, capsid proteins are clients of Hsp90, and Hsp90 inhibitors reduce viral replication because capsid proteins become misfolded and are targeted for degradation.…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…When tau is not bound to microtubules, it associates with the chaperone Hsp70. The E3 ubiquitin ligase CHIP interacts with Hsp70 and promotes tau ubiquitination and degradation 93 . Furthermore, the inhibition of the proteasome-associated deubiquitinating enzyme Usp14 promotes tau degradation 94 .…”