p62 serves as a shuttling factor for TrkA interaction with the proteasome.
The scaffold protein p62 is involved in internalization and trafficking of TrkA. The receptor is deubiquitinated by the proteasomes prior to degradation by lysosomes. Here we demonstrate that p62 serves as a shuttling protein for interaction of ubiquitinated TrkA with Rpt1, one of the six ATPases of 19S regulatory particle of the 26S proteasome. In p62(-/-) mouse brain TrkA failed to interact with the Rpt1. The interaction of TrkA with Rpt1 was reduced in proteasomes isolated from p62(-/-) brain, but was restored by addition of p62. The UBA domain of p62 interacts with TrkA and its PB1/UbL domain with AAA-ATPase cassette in the C-terminal region of Rpt1. Last, neurotrophin-dependent turnover of TrkA was impaired by reduction in the level of p62. These findings reveal that p62 serves as a shuttling factor for interaction of ubiquitinated substrates with the proteasome and could promote localized protein turnover in neurons.
Geetha
Thangiah
T
Department of Biological Sciences, Program in Cellular and Molecular Biosciences, Auburn University, Auburn, AL 36849, USA.
Seibenhener
M Lamar
ML
Chen
Li
L
Madura
Kiran
K
Wooten
Marie W
MW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020917:Receptor, trkA / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C528084:TRIM30 alpha protein, mouse; D020917:Receptor, trkA; D046988:Proteasome Endopeptidase Complex