Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation.
Inclusions isolated from several neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by ubiquitin-positive proteinaceous aggregates. Employing confocal and immunoelectron microscopy, we find that the ubiquitin-associating protein sequestosome1/p62, co-localizes to aggregates isolated from AD but not control brain, along with the E3 ubiquitin ligase, TRAF6. This interaction could be recapitulated by co-transfection in HEK293 cells. Employing both in vitro and in vivo approaches, tau was found to be a substrate of the TRAF6, possessing lysine 63 polyubiquitin chains. Moreover, tau recovered from brain of TRAF6 knockout mice, compared with wild type, was not ubiquitinated. Tau degradation took place through the ubiquitin-proteasome pathway and was dependent upon either the K63-polyubiquitin chains or upon p62. In brain lysates of p62 knockout mice, tau fails to co-interact with Rpt1, a proteasomal subunit, thereby indicating a requirement for p62 shuttling of tau to the proteasome. Our results demonstrate that p62 interacts with K63-polyubiquitinated tau through its UBA domain and serves a novel role in regulating tau proteasomal degradation. We propose a model whereby either a decline in p62 expression or a decrease in proteasome activity may contribute to accumulation of insoluble/aggregated K63-polyubiquitinated tau.
Babu
Jeganathan Ramesh
JR
Department of Biological Sciences, Program in Cell and Molecular Biosciences, Auburn University, AL 36849, USA.
Geetha
Thangiah
T
Wooten
Marie W
MW
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000818:Animals; D002460:Cell Line; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D016716:PC12 Cells; D025821:Polyubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051381:Rats; D000071456:Sequestosome-1 Protein; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016875:tau Proteins; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex