Akt and CHIP coregulate tau degradation through coordinated interactions

Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3622-7. doi: 10.1073/pnas.0709180105. Epub 2008 Feb 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease
  • Animals
  • Cell Cycle Proteins / metabolism
  • HSP90 Heat-Shock Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / deficiency
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / metabolism*
  • tau Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • HSP90 Heat-Shock Proteins
  • tau Proteins
  • Stub1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Mark2 protein, mouse
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt