The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation

Aichem, Annette; Kalveram, Birte; Spinnenhirn, Valentina; Kluge, Kathrin; Catone, Nicola; Johansen, Terje; Gröttrup, Marcus

The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation

Dateien

Aichem_219921.pdfGröße: 1.23 MBDownloads: 315

Datum

2012

Autor:innen

Aichem, Annette

Kalveram, Birte

Spinnenhirn, Valentina

Kluge, Kathrin

Catone, Nicola

Johansen, Terje

Gröttrup, Marcus

Publikationstyp

Zeitschriftenartikel

unikn.publication.listelement.citation.prefix.version.undefined

Journal of Cell Science. 2012, 125(19), pp. 4576-4585. ISSN 0021-9533. eISSN 1477-9137. Available under: doi: 10.1242/jcs.107789

Zusammenfassung

FAT10 is a ubiquitin-like modifier proposed to function in apoptosis induction, cell cycle control and NF-kB activation. Upon induction by pro-inflammatory cytokines, hundreds of endogenous substrates become covalently conjugated to FAT10 leading to their proteasomal degradation. Nevertheless, only three substrates have been identified so far to which FAT10 becomes covalently attached through a non-reducible isopeptide bond, and these are the FAT10-conjugating enzyme USE1 which auto-FAT10ylates itself in cis, the tumor suppressor p53 and the ubiquitin-activating enzyme UBE1 (UBA1). To identify additional FAT10 substrates and interaction partners, we used a new monoclonal FAT10-specific antibody to immunopurify endogenous FAT10 conjugates from interferon (IFN)cand tumor necrosis factor (TNF)alpha-stimulated cells for identification by mass spectrometry. In addition to two already known FAT10- interacting proteins, histone deacetylase 6 and UBA6, we identified 569 novel FAT10-interacting proteins involved in different functional pathways such as autophagy, cell cycle regulation, apoptosis and cancer. Thirty-one percent of all identified proteins were
categorized as putative covalently linked substrates. One of the identified proteins, the autophagosomal receptor p62/SQSTM1, was further investigated. p62 becomes covalently mono-FAT10ylated at several lysines, and FAT10 colocalizes with p62 in p62 bodies.
Strikingly, FAT10ylation of p62 leads to its proteasomal degradation, and prolonged induction of endogenous FAT10 expression by proinflammatory cytokines leads to a decrease of endogenous p62. The elucidation of the FAT10 degradome should enable a better understanding of why FAT10 has evolved as an additional transferable tag for proteasomal degradation.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

Ubiquitin, Proteasome, FAT10, Proteomics, p62

Zitieren

ISO 690

AICHEM, Annette, Birte KALVERAM, Valentina SPINNENHIRN, Kathrin KLUGE, Nicola CATONE, Terje JOHANSEN, Marcus GRÖTTRUP, 2012. The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation. In: Journal of Cell Science. 2012, 125(19), pp. 4576-4585. ISSN 0021-9533. eISSN 1477-9137. Available under: doi: 10.1242/jcs.107789

BibTex

@article{Aichem2012-10-01prote-21992,
  year={2012},
  doi={10.1242/jcs.107789},
  title={The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation},
  number={19},
  volume={125},
  issn={0021-9533},
  journal={Journal of Cell Science},
  pages={4576--4585},
  author={Aichem, Annette and Kalveram, Birte and Spinnenhirn, Valentina and Kluge, Kathrin and Catone, Nicola and Johansen, Terje and Gröttrup, Marcus}
}

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