A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.
Autophagy is a catabolic process where cytosolic cellular components are delivered to the lysosome for degradation. Recent studies have indicated the existence of specific receptors, such as p62, which link ubiquitinated targets to autophagosomal degradation pathways. Here we show that NBR1 (neighbor of BRCA1 gene 1) is an autophagy receptor containing LC3- and ubiquitin (Ub)-binding domains. NBR1 is recruited to Ub-positive protein aggregates and degraded by autophagy depending on an LC3-interacting region (LIR) and LC3 family modifiers. Although NBR1 and p62 interact and form oligomers, they can function independently, as shown by autophagosomal clearance of NBR1 in p62-deficient cells. NBR1 was localized to Ub-positive inclusions in patients with liver dysfunction, and depletion of NBR1 abolished the formation of Ub-positive p62 bodies upon puromycin treatment of cells. We propose that NBR1 and p62 act as receptors for selective autophagosomal degradation of ubiquitinated targets.
Kirkin
Vladimir
V
Institute of Biochemistry II, Goethe University, Frankfurt (Main), Germany.
Lamark
Trond
T
Sou
Yu-Shin
YS
Bjørkøy
Geir
G
Nunn
Jennifer L
JL
Bruun
Jack-Ansgar
JA
Shvets
Elena
E
McEwan
David G
DG
Clausen
Terje H
TH
Wild
Philipp
P
Bilusic
Ivana
I
Theurillat
Jean-Philippe
JP
Øvervatn
Aud
A
Ishii
Tetsuro
T
Elazar
Zvulun
Z
Komatsu
Masaaki
M
Dikic
Ivan
I
Johansen
Terje
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001665:Binding Sites; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C549756:NBR1 protein, human; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D049452:Green Fluorescent Proteins