Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Jan;4(1):85-7.
doi: 10.4161/auto.5172. Epub 2007 Oct 15.

Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway

James A Olzmann  1 , Lih-Shen Chin
Affiliations

Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway

James A Olzmann et al. Autophagy. 2008 Jan.

Abstract

Pathological inclusions containing misfolded proteins are a prominent feature common to many age-related neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In cultured cells, when the production of misfolded proteins exceeds the capacity of the chaperone refolding system and the ubiquitin-proteasome degradation pathway, misfolded proteins are actively transported along microtubules to pericentriolar inclusions called aggresomes. The aggresomes sequester potentially toxic misfolded proteins and facilitate their clearance by autophagy. The molecular mechanism(s) that targets misfolded proteins to the aggresome-autophagy pathway is mostly unknown. Our recent work identifies parkin-mediated K63-linked polyubiquitination as a signal that couples misfolded proteins to the dynein motor complex via the adaptor protein histone deacetylase 6 and thereby promotes sequestration of misfolded proteins into aggresomes and subsequent clearance by autophagy. Our findings provide insight into the mechanisms underlying aggresome formation and suggest that parkin and K63-linked polyubiquitination may play a role in the autophagic clearance of misfolded proteins.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A model of parkin function in the clearance of misfolded proteins by the aggresome-autophagy pathway. Under conditions of proteasomal impairment, parkin coordinates the E2 enzyme UbcH13/Uev1a to mediate K63-linked polyubiquitination of misfolded proteins (step 1). This K63-linked polyubiquitin chain promotes binding to HDAC6 (step 2) and thereby links the ubiquitinated proteins to the dynein motor complex for transport to the aggresome (step 3). Autophagic membrane and machinery are recruited to the aggresome (step 4). The autophagosome then fuses with lysosomes to form an autophagolysosome and thus allows the degradation of misfolded and aggregated proteins by lysosomal hydrolases (step 5).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med. 2004;10(Suppl):S10–7. - PubMed
    1. Garcia-Mata R, Gao YS, Sztul E. Hassles with taking out the garbage: aggravating aggresomes. Traffic. 2002;3:388–96. - PubMed
    1. Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 2000;10:524–30. - PubMed
    1. Holmberg CI, Staniszewski KE, Mensah KN, Matouschek A, Morimoto RI. Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J. 2004;23:4307–18. - PMC - PubMed
    1. Kristiansen M, Deriziotis P, Dimcheff DE, Jackson GS, Ovaa H, Naumann H, Clarke AR, van Leeuwen FW, Menendez-Benito V, Dantuma NP, Portis JL, Collinge J, Tabrizi SJ. Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol Cell. 2007;26:175–88. - PubMed

Publication types

LinkOut - more resources