Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases.
Although ubiquitin-enriched protein inclusions represent an almost invariant feature of neurodegenerative diseases, the mechanism underlying their biogenesis remains unclear. In particular, whether the topology of ubiquitin linkages influences the dynamics of inclusions is not well explored. Here, we report that lysine 48 (K48)- and lysine 63 (K63)-linked polyubiquitination, as well as monoubiquitin modification contribute to the biogenesis of inclusions. K63-linked polyubiquitin is the most consistent enhancer of inclusions formation. Under basal conditions, ectopic expression of K63 mutant ubiquitin in cultured cells promotes the accumulation of proteins and the formation of intracellular inclusions in the apparent absence of proteasome impairment. When co-expressed with disease-associated tau and SOD1 mutants, K63 ubiquitin mutant facilitates the formation of tau- and SOD-1-positive inclusions. Moreover, K63-linked ubiquitination was found to selectively facilitate the clearance of inclusions via autophagy. These data indicate that K63-linked ubiquitin chains may represent a common denominator underlying inclusions biogenesis, as well as a general cellular strategy for defining cargo destined for the autophagic system. Collectively, our results provide a novel mechanistic route that underlies the life cycle of an inclusion body. Harnessing this pathway may offer innovative approaches in the treatment of neurodegenerative disorders.
Tan
Jeanne M M
JM
Neurodegeneration Research Lab, National Neuroscience Institute, Singapore, Singapore.
Wong
Esther S P
ES
Kirkpatrick
Donald S
DS
Pletnikova
Olga
O
Ko
Han Seok
HS
Tay
Shiam-Peng
SP
Ho
Michelle W L
MW
Troncoso
Juan
J
Gygi
Steven P
SP
Lee
Michael K
MK
Dawson
Valina L
VL
Dawson
Ted M
TM
Lim
Kah-Leong
KL
D001343:Autophagy; D002460:Cell Line; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection; D025801:Ubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D025801:Ubiquitin; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008239:Lysine