Disruption of the chaperonin containing TCP-1 function affects protein networks essential for rod outer segment morphogenesis and survival.
Type II Chaperonin Containing TCP-1 (CCT, also known as TCP-1 Ring Complex, TRiC) is a multi-subunit molecular machine thought to assist in the folding of ∼ 10% of newly translated cytosolic proteins in eukaryotes. A number of proteins folded by CCT have been identified in yeast and cultured mammalian cells, however, the function of this chaperonin in vivo has never been addressed. Here we demonstrate that suppressing the CCT activity in mouse photoreceptors by transgenic expression of a dominant-negative mutant of the CCT cofactor, phosducin-like protein (PhLP), results in the malformation of the outer segment, a cellular compartment responsible for light detection, and triggers rapid retinal degeneration. Investigation of the underlying causes by quantitative proteomics identified distinct protein networks, encompassing ∼ 200 proteins, which were significantly affected by the chaperonin deficiency. Notably among those were several essential proteins crucially engaged in structural support and visual signaling of the outer segment such as peripherin 2, Rom1, rhodopsin, transducin, and PDE6. These data for the first time demonstrate that normal CCT function is ultimately required for the morphogenesis and survival of sensory neurons of the retina, and suggest the chaperonin CCT deficiency as a potential, yet unexplored, cause of neurodegenerative diseases.
Posokhova
Ekaterina
E
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Song
Hongman
H
Belcastro
Marycharmain
M
Higgins
LeeAnn
L
Bigley
Lauren R
LR
Michaud
Norman A
NA
Martemyanov
Kirill A
KA
Sokolov
Maxim
M
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival; D056404:Chaperonin Containing TCP-1 / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D015536:Down-Regulation; D055537:Light Signal Transduction; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009024:Morphogenesis; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D012374:Rod Cell Outer Segment / Q000378:metabolism* / Q000648:ultrastructure
D002352:Carrier Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; C498319:Pdcl protein, mouse; D020543:Proteome; D056404:Chaperonin Containing TCP-1