Intracellular antibody signalling is regulated by phosphorylation of the Fc receptor TRIM21

Cell surface Fc receptors activate inflammation and are tightly controlled to prevent autoimmunity. Antibodies also simulate potent immune signalling from inside the cell via the cytosolic antibody receptor TRIM21, but how this is regulated is unknown. Here we show that TRIM21 signalling is constitutively repressed by its B-Box domain and activated by phosphorylation. The B-Box occupies an E2 binding site on the catalytic RING domain by mimicking E2-E3 interactions, inhibiting TRIM21 ubiquitination and preventing immune activation. TRIM21 is derepressed by IKKβ and TBK1 phosphorylation of an LxxIS motif in the RING domain, at the interface with the B-Box. Incorporation of phosphoserine or a phosphomimetic within this motif relieves B-Box inhibition, promoting E2 binding, RING catalysis, NF-κB activation and cytokine transcription upon infection with DNA or RNA viruses. These data explain how intracellular antibody signalling is regulated and reveal that the B-Box is a critical regulator of RING E3 ligase activity.

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Regulation of ubiquitin transfer by XIAP, a dimeric RING E3 ligase

Biochemical Journal ◽

10.1042/bj20121702 ◽

2013 ◽

Vol 450 (3) ◽

pp. 629-638 ◽

Cited By ~ 34

Author(s):

Yoshio Nakatani ◽

Torsten Kleffmann ◽

Katrin Linke ◽

Stephen M. Condon ◽

Mark G. Hinds ◽

...

Keyword(s):

Biochemical Analysis ◽

E3 Ligase ◽

Ring Domain ◽

Aromatic Residue ◽

E3 Ligases ◽

Dimer Interface ◽

Ring E3 Ligase ◽

Thioester Bond ◽

Ring E3 ◽

Apoptosis Proteins

RING domains of E3 ligases promote transfer of Ub (ubiquitin) from the E2~Ub conjugate to target proteins. In many cases interaction of the E2~Ub conjugate with the RING domain requires its prior dimerization. Using cross-linking experiments we show that E2 conjugated ubiquitin contacts the RING homodimer interface of the IAP (inhibitor of apoptosis) proteins, XIAP (X-linked IAP) and cIAP (cellular IAP) 2. Structural and biochemical analysis of the XIAP RING dimer shows that an aromatic residue at the dimer interface is required for E2~Ub binding and Ub transfer. Mutation of the aromatic residue abolishes Ub transfer, but not interaction with Ub. This indicates that nuleophilic attack on the thioester bond depends on precise contacts between Ub and the RING domain. RING dimerization is a critical activating step for the cIAP proteins; however, our analysis shows that the RING domain of XIAP forms a stable dimer and its E3 ligase activity does not require an activation step.

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OsDIRP1, a Putative RING E3 Ligase, Plays an Opposite Role in Drought and Cold Stress Responses as a Negative and Positive Factor, Respectively, in Rice (Oryza sativa L.)

Frontiers in Plant Science ◽

10.3389/fpls.2018.01797 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 7

Author(s):

Li Hua Cui ◽

Hye Jo Min ◽

Mi Young Byun ◽

Hyeong Geun Oh ◽

Woo Taek Kim

Keyword(s):

Oryza Sativa ◽

Cold Stress ◽

Stress Responses ◽

Oryza Sativa L ◽

E3 Ligase ◽

Ring E3 Ligase ◽

Ring E3 ◽

Positive Factor

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A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation

Science ◽

10.1126/science.aaw4912 ◽

2019 ◽

Vol 365 (6448) ◽

pp. eaaw4912 ◽

Cited By ~ 27

Author(s):

Richard T. Timms ◽

Zhiqian Zhang ◽

David Y. Rhee ◽

J. Wade Harper ◽

Itay Koren ◽

...

Keyword(s):

Quality Control ◽

Protein Stability ◽

Protein Degradation ◽

E3 Ligase ◽

Cleavage Sites ◽

Caspase Cleavage ◽

E3 Ligases ◽

Ring E3 Ligase ◽

The Stability ◽

Ring E3

The N-terminal residue influences protein stability through N-degron pathways. We used stability profiling of the human N-terminome to uncover multiple additional features of N-degron pathways. In addition to uncovering extended specificities of UBR E3 ligases, we characterized two related Cullin-RING E3 ligase complexes, Cul2ZYG11B and Cul2ZER1, that act redundantly to target N-terminal glycine. N-terminal glycine degrons are depleted at native N-termini but strongly enriched at caspase cleavage sites, suggesting roles for the substrate adaptors ZYG11B and ZER1 in protein degradation during apoptosis. Furthermore, ZYG11B and ZER1 were found to participate in the quality control of N-myristoylated proteins, in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation. Thus, an additional N-degron pathway specific for glycine regulates the stability of metazoan proteomes.

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