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Gene Review

PDCD6IP  -  programmed cell death 6 interacting protein

Homo sapiens

Synonyms: AIP1, ALG-2-interacting protein 1, ALG-2-interacting protein X, ALIX, Alix, ...
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Disease relevance of PDCD6IP

  • AIP1 also binds the HIV-1 p6(Gag) and EIAV p9(Gag) proteins, indicating that it can function directly in virus budding [1].
  • Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma [2].
  • Alix labelling was increased in neuronal cell bodies in kainate-sensitive regions before or concomitant with the first signs of oedema and/or neuronal eosinophilia [3].
  • EIAV (equine infectious anaemia virus) and HIV late domains use Alix to recruit the ESCRT machinery in order to bud from the cell surface, underscoring the crucial role of the protein in orchestrating membrane deformation [4].
  • Rapid actin monomer-insensitive depolymerization of Listeria actin comet tails by cofilin, coronin, and Aip1 [5].

Psychiatry related information on PDCD6IP


High impact information on PDCD6IP

  • This last step, which initiates infection, depends on the late endosomal lipid lysobisphosphatidic acid (LBPA) and its putative effector Alix/AIP1, and is regulated by phosphatidylinositol-3-phosphate (PtdIns3P) signalling via the PtdIns3P-binding protein Snx16 [7].
  • The cooperative activities of cofilin, coronin, and Aip1 should provide a biochemical basis for understanding how actin filaments can grow in some places in the cell while shrinking in others [5].
  • By biochemical fractionation, we identify Aip1 and coronin as two proteins present in thymus extract that facilitate the cofilin-mediated disassembly of Listeria comet tails [5].
  • In agreement with this, small interfering RNA-mediated knockdown of Alix promoted EGFR internalization and downregulation [8].
  • Here, we report that paraptosis, an alternative, nonapoptotic cell death program that may be induced by the insulin-like growth factor I receptor (among other inducers), is mediated by mitogen-activated protein kinases (MAPKs) and inhibited by AIP-1/Alix [9].

Biological context of PDCD6IP


Anatomical context of PDCD6IP

  • Furthermore, CHMP4b co-localized with SKD1(E235Q) as punctate patterns in the perinuclear area, and Alix was induced to exhibit dot-like distributions overlapped with SKD1(E235Q) in HeLa cells [10].
  • Depletion of Alix caused a striking redistribution of early endosomes from a peripheral to a perinuclear location [12].
  • Although there was no evidence for direct molecular interactions between SETA and cytoskeletal proteins, the SETA-interacting protein AIP1, which is a rat ortholog of the Xenopus src substrate Xp95, strongly interacted with structural proteins of the cytoskeleton, including actin and tubulins [11].
  • SETA, which interacted as a dimer with focal adhesion kinases, promoted the interaction between PYK-2 and AIP1 [11].
  • ALG-2 and its putative target molecule, Alix/AIP1, are localized primarily in the cytoplasm of melanocytes and melanoma cells independent of the intracellular Ca(2+) concentration or the activation of apoptosis [2].

Associations of PDCD6IP with chemical compounds

  • The interaction of Alix with CHMP4b was confirmed by a glutathione S-transferase pull-down assay and by co-immunoprecipitation experiments [10].
  • The yeast two-hybrid system and a biotin-tagged ALG-2 overlay assay were carried out to characterize the interaction between ALG-2 and Alix [14].
  • We examined Alix expression 2 h, 6 h and 24 h after triggering seizure-dependent neuronal death by i.p. kainic acid injection [3].
  • Role of LBPA and Alix in multivesicular liposome formation and endosome organization [15].
  • Alix/AIP1 is an adaptor protein involved in regulating the function of receptor and cytoskeleton-associated tyrosine kinases [16].

Physical interactions of PDCD6IP

  • These results suggest that CHMP4b is a major binding partner of Alix among the three CHMP4 isoforms [17].

Enzymatic interactions of PDCD6IP


Regulatory relationships of PDCD6IP

  • Fluorescence microscopic analysis revealed that CHMP4b transiently expressed in HeLa cells mainly exhibited a punctate distribution in the perinuclear area and co-localized with co-expressed Alix [10].
  • ALIX point mutants that block CEP55 and CHMP4/ESCRT-III binding also inhibit abscission, indicating that both interactions are essential [19].
  • Our data establish that ALIX can have a dramatic effect on HIV-1 release and suggest that the ability to use ALIX may allow HIV-1 to replicate in cells that express only low levels of Tsg101 [20].

Other interactions of PDCD6IP

  • By yeast two-hybrid screening using human ALG-2 as bait, we isolated a cDNA of a novel ALG-2-interacting protein, which turned out to be annexin XI [21].
  • Quantitative immunoelectron microscopy showed that multivesicular endosomes of Alix-depleted cells contained normal amounts of CD63, whereas their levels of lysobisphosphatidic acid were reduced [12].
  • We investigated interactions between HD-PTP and Alix-binding proteins [22].
  • Mammalian Alix may have a similar function and has been shown to bind to lyso(bis)phosphatidic acid, ESCRT (endosomal sorting complex required for transport) proteins, endophilins and CIN85 (Cbl-interacting protein of 85 kDa), which are all main regulators of the endosomal system [4].
  • These results suggest that IGFIR-induced paraptosis is mediated by MAPKs, and inhibited by AIP-1/Alix [9].

Analytical, diagnostic and therapeutic context of PDCD6IP

  • Additional immunofluorescence experiments showed that hSnf7-1 recruited cytosolic AIP1 to the Snf7-induced vacuolar-like structures [23].
  • However, binding of Ca(2+) to both EF-1 and EF-3 is necessary for ALG-2 interaction with Alix/AIP1 as demonstrated using surface plasmon resonance spectroscopy [2].
  • By MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight) MS analyses and gel mobility-shift assays, Xp95 is phosphorylated at multiple sites within the N-terminal half of the PRD during Xenopus oocyte maturation, and a similar region in Alix is phosphorylated in mitotically arrested but not serum-stimulated mammalian cells [24].
  • Site-directed mutagenesis suggested that Aip1p has two actin binding sites, the primary actin binding site lies on the edge of its N-terminal beta-propeller and a secondary actin binding site lies in a comparable location on its C-terminal beta-propeller [25].
  • A genetic dissection of Aip1p's interactions leads to a model for Aip1p-cofilin cooperative activities [25].


  1. The protein network of HIV budding. von Schwedler, U.K., Stuchell, M., Müller, B., Ward, D.M., Chung, H.Y., Morita, E., Wang, H.E., Davis, T., He, G.P., Cimbora, D.M., Scott, A., Kräusslich, H.G., Kaplan, J., Morham, S.G., Sundquist, W.I. Cell (2003) [Pubmed]
  2. Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma. Subramanian, L., Crabb, J.W., Cox, J., Durussel, I., Walker, T.M., van Ginkel, P.R., Bhattacharya, S., Dellaria, J.M., Palczewski, K., Polans, A.S. Biochemistry (2004) [Pubmed]
  3. Early increase of apoptosis-linked gene-2 interacting protein X in areas of kainate-induced neurodegeneration. Hemming, F.J., Fraboulet, S., Blot, B., Sadoul, R. Neuroscience (2004) [Pubmed]
  4. Do Alix and ALG-2 really control endosomes for better or for worse? Sadoul, R. Biol. Cell (2006) [Pubmed]
  5. Rapid actin monomer-insensitive depolymerization of Listeria actin comet tails by cofilin, coronin, and Aip1. Brieher, W.M., Kueh, H.Y., Ballif, B.A., Mitchison, T.J. J. Cell Biol. (2006) [Pubmed]
  6. The multiple personalities of Alix. Odorizzi, G. J. Cell. Sci. (2006) [Pubmed]
  7. Endosome-to-cytosol transport of viral nucleocapsids. Le Blanc, I., Luyet, P.P., Pons, V., Ferguson, C., Emans, N., Petiot, A., Mayran, N., Demaurex, N., Fauré, J., Sadoul, R., Parton, R.G., Gruenberg, J. Nat. Cell Biol. (2005) [Pubmed]
  8. Alix/AIP1 antagonizes epidermal growth factor receptor downregulation by the Cbl-SETA/CIN85 complex. Schmidt, M.H., Hoeller, D., Yu, J., Furnari, F.B., Cavenee, W.K., Dikic, I., Bögler, O. Mol. Cell. Biol. (2004) [Pubmed]
  9. Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Sperandio, S., Poksay, K., de Belle, I., Lafuente, M.J., Liu, B., Nasir, J., Bredesen, D.E. Cell Death Differ. (2004) [Pubmed]
  10. The ALG-2-interacting protein Alix associates with CHMP4b, a human homologue of yeast Snf7 that is involved in multivesicular body sorting. Katoh, K., Shibata, H., Suzuki, H., Nara, A., Ishidoh, K., Kominami, E., Yoshimori, T., Maki, M. J. Biol. Chem. (2003) [Pubmed]
  11. SETA/CIN85/Ruk and its binding partner AIP1 associate with diverse cytoskeletal elements, including FAKs, and modulate cell adhesion. Schmidt, M.H., Chen, B., Randazzo, L.M., Bogler, O. J. Cell. Sci. (2003) [Pubmed]
  12. Alix regulates cortical actin and the spatial distribution of endosomes. Cabezas, A., Bache, K.G., Brech, A., Stenmark, H. J. Cell. Sci. (2005) [Pubmed]
  13. Hp95 promotes anoikis and inhibits tumorigenicity of HeLa cells. Wu, Y., Pan, S., Luo, W., Lin, S.H., Kuang, J. Oncogene (2002) [Pubmed]
  14. The penta-EF-hand protein ALG-2 interacts with a region containing PxY repeats in Alix/AIP1, which is required for the subcellular punctate distribution of the amino-terminal truncation form of Alix/AIP1. Shibata, H., Yamada, K., Mizuno, T., Yorikawa, C., Takahashi, H., Satoh, H., Kitaura, Y., Maki, M. J. Biochem. (2004) [Pubmed]
  15. Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Matsuo, H., Chevallier, J., Mayran, N., Le Blanc, I., Ferguson, C., Fauré, J., Blanc, N.S., Matile, S., Dubochet, J., Sadoul, R., Parton, R.G., Vilbois, F., Gruenberg, J. Science (2004) [Pubmed]
  16. Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. Schmidt, M.H., Dikic, I., Bögler, O. J. Biol. Chem. (2005) [Pubmed]
  17. CHMP4b is a major binding partner of the ALG-2-interacting protein Alix among the three CHMP4 isoforms. Katoh, K., Shibata, H., Hatta, K., Maki, M. Arch. Biochem. Biophys. (2004) [Pubmed]
  18. Alix and ALG-2 are involved in tumor necrosis factor receptor 1-induced cell death. Mahul-Mellier, A.L., Strappazzon, F., Petiot, A., Chatellard-Causse, C., Torch, S., Blot, B., Freeman, K., Kuhn, L., Garin, J., Verna, J.M., Fraboulet, S., Sadoul, R. J. Biol. Chem. (2008) [Pubmed]
  19. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. Morita, E., Sandrin, V., Chung, H.Y., Morham, S.G., Gygi, S.P., Rodesch, C.K., Sundquist, W.I. EMBO J. (2007) [Pubmed]
  20. Potent rescue of human immunodeficiency virus type 1 late domain mutants by ALIX/AIP1 depends on its CHMP4 binding site. Usami, Y., Popov, S., Göttlinger, H.G. J. Virol. (2007) [Pubmed]
  21. ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca(2+)-dependent manner. Satoh, H., Shibata, H., Nakano, Y., Kitaura, Y., Maki, M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  22. HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions. Ichioka, F., Takaya, E., Suzuki, H., Kajigaya, S., Buchman, V.L., Shibata, H., Maki, M. Arch. Biochem. Biophys. (2007) [Pubmed]
  23. Structure and function of human Vps20 and Snf7 proteins. Peck, J.W., Bowden, E.T., Burbelo, P.D. Biochem. J. (2004) [Pubmed]
  24. Phosphorylation of the proline-rich domain of Xp95 modulates Xp95 interaction with partner proteins. Dejournett, R.E., Kobayashi, R., Pan, S., Wu, C., Etkin, L.D., Clark, R.B., B??gler, O., Kuang, J. Biochem. J. (2007) [Pubmed]
  25. A genetic dissection of Aip1p's interactions leads to a model for Aip1p-cofilin cooperative activities. Clark, M.G., Teply, J., Haarer, B.K., Viggiano, S.C., Sept, D., Amberg, D.C. Mol. Biol. Cell (2006) [Pubmed]
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