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First published online 3 August 2004
doi: 10.1242/jcs.01287

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Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes

Anne Simonsen^1,, Hanne C. G. Birkeland^1,, David J. Gillooly¹, Noboru Mizushima^2,3,*, Akiko Kuma^2,3, Tamotsu Yoshimori^4,5, Thomas Slagsvold¹, Andreas Brech¹ and Harald Stenmark^1,

¹ Department of Biochemistry, The Norwegian Radium Hospital, Montebello, Oslo, 0310, Norway
² Department of Cell Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaijicho, Okazaki 444-8585, Japan
³ PRESTO, Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
⁴ CREST, Japan Science and Technology Agency, Kawaguchi Center Building, 4-1-8, Honcho, Kawaguchi-shi, Saitama 332-0012, Japan
⁵ Department of Cell Genetics, National Institute of Genetics, Yata 1111 Mishima, Shizuoka-ken, 411-8540, Japan

Author for correspondence (e-mail: stenmark{at}ulrik.uio.no)

Accepted 22 April 2004

Phosphatidylinositol-3-phosphate [PtdIns(3)P] regulates endocytic and autophagic membrane traffic. In order to understand the downstream effects of PtdIns(3)P in these processes, it is important to identify PtdIns(3)P-binding proteins, many of which contain FYVE zinc-finger domains. Here, we describe a novel giant FYVE-domain-containing protein, named autophagy-linked FYVE protein (Alfy). Alfy is ubiquitously expressed, shares sequence similarity with the Chediak-Higashi-syndrome protein and has putative homologues in flies, nematodes and fission yeast. Alfy binds PtdIns(3)P in vitro and partially colocalizes with PtdIns(3)P in vivo. Unlike most other FYVE-domain proteins, Alfy is not found on endosomes but instead localizes mainly to the nuclear envelope. When HeLa cells are starved or treated with a proteasome inhibitor, Alfy relocalizes to characteristic filamentous cytoplasmic structures located close to autophagic membranes and ubiquitin-containing protein aggregates. By electron microscopy, similar structures can be found within autophagosomes. We propose that Alfy might target cytosolic protein aggregates for autophagic degradation.

Key words: Aggresome, Atg5, Autophagy, BEACH domain, FYVE domain, PI-3-kinase

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