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J. Biol. Chem., Vol. 282, Issue 33, 24131-24145, August 17, 2007

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p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy^*

Serhiy Pankiv, Terje Høyvarde Clausen, Trond Lamark, Andreas Brech¹, Jack-Ansgar Bruun, Heidi Outzen, Aud Øvervatn, Geir Bjørkøy, and Terje Johansen²

From the Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø and the Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello N-0310, Oslo, Norway

Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of neurodegenerative diseases. The polyubiquitin-binding protein p62/SQSTM1 is degraded by autophagy. It is found in cellular inclusion bodies together with polyubiquitinated proteins and in cytosolic protein aggregates that accumulate in various chronic, toxic, and degenerative diseases. Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B and the related -aminobutyrate receptor-associated protein and -aminobutyrate receptor-associated-like proteins. The binding is mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif. To monitor the autophagic sequestration of p62- and LC3-positive bodies, we developed a novel pH-sensitive fluorescent tag consisting of a tandem fusion of the red, acid-insensitive mCherry and the acid-sensitive green fluorescent proteins. This approach revealed that p62- and LC3-positive bodies are degraded in autolysosomes. Strikingly, even rather large p62-positive inclusion bodies (2 µm diameter) become degraded by autophagy. The specific interaction between p62 and LC3, requiring the motif we have mapped, is instrumental in mediating autophagic degradation of the p62-positive bodies. We also demonstrate that the previously reported aggresome-like induced structures containing ubiquitinated proteins in cytosolic bodies are dependent on p62 for their formation. In fact, p62 bodies and these structures are indistinguishable. Taken together, our results clearly suggest that p62 is required both for the formation and the degradation of polyubiquitin-containing bodies by autophagy.

Received for publication, April 3, 2007 , and in revised form, May 18, 2007.

^* This work was supported in part by grants from the FUGE and "Top Research Programme" of the Norwegian Research Council, the Norwegian Cancer Society, the Aakre Foundation, Simon Fougner Hartmanns Familiefond, and the Blix Foundation (to T. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5.

¹ Recipient of a career fellowship from the FUGE programme of the Norwegian Research Council.

² To whom correspondence should be addressed: Dept. of Biochemistry, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway. Tel.: 47-776-44720; Fax: 47-776-45350; E-mail: terjej{at}fagmed.uit.no.

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