Ubiquitin and Ub-like interactomes in regulation of cellular functions
Zusammenfassung der Projektergebnisse
Protein ubiquitylation (ubiquitination), the attachment of a small polypeptide ubiquitin (Ub) to protein substrates, is an evolutionary conserved mechanism that controls a wide variety of cellular functions, including proteasomal degradation, intracellular trafficking, DNA repair, gene transcription and virus budding. In addition to Ub there are several Ub-like modifiers, e.g. SUMO, FAT10, ISG15, ATG8 and ATG12, etc., which trigger various cellular responses. Similar to the Ub-system the control of these processes requires proteins that are able to recognize the Ubl and link the modified protein to a downstream pathway. Moreover, a crosstalk between different Ubls might exist. Using yeast-two-hybrid screens we have identified and characterized several new Ub and Ubl-binding domains that are present in various types of proteins: 1) We have discovered a novel type of UBD in Rpn13, which we termed Pru domain. Mutational analyses of Pru and yeast genetics revealed that Rpn13 acts as a proteasomal receptor involved in the degradation of ubiquitinated proteins. The corresponding publication was commented by a News and views article. 2) We identified novel Ub-binding domains (UBAN) in ABIN proteins that are able to inhibit NF-kappaB. Loss-of-function UBAN mutants impaired the NF-kappaB inhibitory potential of ABINs. 3) The UBAN domain is also present in NEMO. It selectively binds to linear (head-totail) Ub chains and is required for NF-kappaB activation by TNF-α and other agonists. 4) We have shown that NBR1 is an autophagy receptor containing LC3- and ubiquitin (Ub)-binding domains. Our data suggest that NBR1 acts as receptor for selective autophagosomal degradation of ubiquitinated targets.
Projektbezogene Publikationen (Auswahl)
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Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 2008, 453:481-488
Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters K, Finley D, Dikic I
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Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins. Oncogene 2008, 27:3739-45
Wagner S, Carpentier I, Rogov V, Kreike M, Ikeda F, Löhr F, Wu CJ, Ashwell JD, Dötsch V, Dikic I, Beyaert R
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Ubiquitin docking at the proteasome via a novel PH domain interaction. Nature, 453:548-552, 2008
Schreiner P, Chen X, Husnjak K, Randles L, Zhang N, Elsasser S, Finley D, Dikic I, Walters K, Groll M
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A role for NBR1 is autophagosomal degradation of ubiquitinated substrates, Mol Cell 2009, 33(4):505-16
Kirkin V, Lamark T, Sou Y, Bjørkøy G, Nunn J, Bruun JA, Shvets E, McEwan DG, Clausen TH, Wild P, Bilusic I, Theurillat JP, Øvervatn A, Ishii T, Elazar Z, Komatsu M, Dikic I, Johansen T
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Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 2009, 136(6):1098- 109
Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, Kensche T, Uejima T, Bloor S, Komander D, Randow F, Wakatsuki S and Dikic I
