Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly.
Phosphorylation regulates both normal and pathological Tau functioning. This microtubule-associated protein plays a role in the organization and integrity of the neuronal cytoskeleton under normal conditions and becomes hyperphosphorylated and aggregated in a number of neurodegenerative diseases referred to as tauopathies. In this study, we identify and compare the residues in human Tau phosphorylated in vitro by all four p38 MAPK isoforms, and study the regulation of the phosphorylation of Thr50, under conditions where p38 MAPKs are active in cells. Through biochemical analysis, loss of function studies and analysis of endogenous and overexpressed Tau proteins, we show that SAPK4/p38delta is the major kinase phosphorylating Thr50 in Tau, when cells are exposed to osmotic stress. We also show that mutation of Thr50 to glutamic acid, which mimics phosphorylation, increases the ability of Tau to promote tubulin polymerisation in vitro and in vivo. Moreover, we show that Thr50 is phosphorylated in filamentous Tau from Alzheimer's disease brain. These findings suggest a role for Tau in the adaptative response of neurons to stress and indicate that SAPK4/p38delta and/or SAPK3/p38delta may contribute to the hyperphosphorylation of Tau in the human tauopathies.
Feijoo
Carmen
C
MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Campbell
David G
DG
Jakes
Ross
R
Goedert
Michel
M
Cuenda
Ana
A
D002460:Cell Line; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D013912:Threonine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism / Q000502:physiology*
D020033:Protein Isoforms; D016875:tau Proteins; D013912:Threonine; D048292:Mitogen-Activated Protein Kinase 13; D048051:p38 Mitogen-Activated Protein Kinases