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Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme.

A20 is an anti-inflammatory protein linked to multiple human autoimmune diseases and lymphomas. A20 possesses a deubiquitinating motif and a zinc finger, ZF4, that binds ubiquitin and supports its E3 ubiquitin ligase activity. To understand how these activities mediate A20's physiological functions, we generated two lines of gene-targeted mice, abrogating either A20's deubiquitinating activity (Tnfaip3(OTU) mice) or A20's ZF4 (Tnfaip3(ZF4) mice). Both Tnfaip3(OTU) and Tnfaip3(ZF4) mice exhibited increased responses to TNF and sensitivity to colitis. A20's C103 deubiquitinating motif restricted both K48- and K63-linked ubiquitination of receptor interacting protein 1 (RIP1). A20's ZF4 was required for recruiting A20 to ubiquitinated RIP1. A20(OTU) proteins and A20(ZF4) proteins complemented each other to regulate RIP1 ubiquitination and NFκB signaling normally in compound mutant Tnfaip3(OTU/ZF4) cells. This complementation involved homodimerization of A20 proteins, and we have defined an extensive dimerization interface in A20. These studies reveal how A20 proteins collaborate to restrict TNF signaling.

Pubmed ID: 23602765

Authors

  • Lu TT
  • Onizawa M
  • Hammer GE
  • Turer EE
  • Yin Q
  • Damko E
  • Agelidis A
  • Shifrin N
  • Advincula R
  • Barrera J
  • Malynn BA
  • Wu H
  • Ma A

Journal

Immunity

Publication Data

May 23, 2013

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P30 DK026743
  • Agency: NIAID NIH HHS, Id: R01 AI045937
  • Agency: NIDDK NIH HHS, Id: R01 DK071939

Mesh Terms

  • Animals
  • Cells, Cultured
  • Colitis
  • Cysteine Endopeptidases
  • DNA-Binding Proteins
  • GTPase-Activating Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Multimerization
  • Signal Transduction
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Zinc Fingers