The Glomuvenous Malformation Protein Glomulin Binds Rbx1 and Regulates Cullin RING Ligase-Mediated Turnover of Fbw7

Tron, Adriana E.; Arai, Takehiro; Duda, David M.; Kuwabara, Hiroshi; Olszewski, Jennifer L.; Fujiwara, Yuko; Bahamón, Brittany; Signoretti, Sabina; Schulman, Brenda A.; DeCaprio, James A.

doi:10.1016/j.molcel.2012.02.005

Cited by 58 publications

(67 citation statements)

References 44 publications

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“…S6 B and C). Consistent with findings in other studies (50), GLMN +/− mice were healthy, fertile, and had no visible disorders, whereas GLMN −/− embryos at embryonic day (E)7.5-E10.5 were fleshy masses that did not undergo further development. Therefore, we examined Shigellainduced cytotoxicity and IL-1β secretion in BMDMs from GLMN +/− and GLMN +/+ mice.…”

Section: Glmn Dampens Inflammasome Activation and Macrophage Pyroptosissupporting

confidence: 89%

“…GLMN originally was identified as a gene responsible for familial glomuvenous malformations, a disorder that results in localized cutaneous vascular lesions because of loss-of-function mutations in the Glmn gene (45)(46)(47)(48). More recently, GLMN was characterized as a Cullin ring ligase inhibitor that blocks interaction with its ubiquitin-conjugating enzyme (E2) (49,50).…”

Section: Resultsmentioning

confidence: 99%

“…The same group recently reported that GLMN binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity (49,50). Rbx1 regulates the cullin RING ligase-mediated turnover of Fbw7, a substrate receptor for Cul1-RING-CRL, which facilitates the ubiquitination and degradation of cyclin E and c-Myc (49,50). If this activity also is involved in the GLMN-inflammasome interplay, GLMN may suppress NLR inflammasome activation, e.g., by interacting with and inhibiting a hypothetical E3 ubiquitin ligase that activates the inflammasome.…”

Section: Discussionmentioning

confidence: 96%

“…Cullins are subunits of the cullin RING ligase (CRL) family. The same group recently reported that GLMN binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity (49,50). Rbx1 regulates the cullin RING ligase-mediated turnover of Fbw7, a substrate receptor for Cul1-RING-CRL, which facilitates the ubiquitination and degradation of cyclin E and c-Myc (49,50).…”

Section: Discussionmentioning

confidence: 99%

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Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Suzuki

Mimuro

Kim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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When nucleotide-binding oligomerization domain-like receptors (NLRs) sense cytosolic-invading bacteria, they induce the formation of inflammasomes and initiate an innate immune response. In quiescent cells, inflammasome activity is tightly regulated to prevent excess inflammation and cell death. Many bacterial pathogens provoke inflammasome activity and induce inflammatory responses, including cell death, by delivering type III secreted effectors, the rod component flagellin, and toxins. Recent studies indicated that Shigella deploy multiple mechanisms to stimulate NLR inflammasomes through type III secretion during infection. Here, we show that Shigella induces rapid macrophage cell death by delivering the invasion plasmid antigen H7.8 (IpaH7.8) enzyme 3 (E3) ubiquitin ligase effector via the type III secretion system, thereby activating the NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing 4 (NLRC4) inflammasomes and caspase-1 and leading to macrophage cell death in an IpaH7.8 E3 ligase-dependent manner. Mice infected with Shigella possessing IpaH7.8, but not with Shigella possessing an IpaH7.8 E3 ligase-null mutant, exhibited enhanced bacterial multiplication. We defined glomulin/flagellar-associated protein 68 (GLMN) as an IpaH7.8 target involved in IpaH7.8 E3 ligase-dependent inflammasome activation. This protein originally was identified through its association with glomuvenous malformations and more recently was described as a member of a Cullin ring ligase inhibitor. Modifying GLMN levels through overexpression or knockdown led to reduced or augmented inflammasome activation, respectively. Macrophages stimulated with lipopolysaccharide/ATP induced GLMN puncta that localized with the active form of caspase-1. Macrophages from GLMN +/− mice were more responsive to inflammasome activation than those from GLMN +/+ mice. Together, these results highlight a unique bacterial adaptation that hijacks inflammasome activation via interactions between IpaH7.8 and GLMN.

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Section: Glmn Dampens Inflammasome Activation and Macrophage Pyroptosissupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Suzuki

Mimuro

Kim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…7C). Considering that the product species "d" is about 60 kDa larger than the input substrate ␤-cat-Lys-63-Ub 16 (Fig. 7C, lanes 4 and 5), it suggests that SCF ␤TrCP /Cdc34 is able to conjugate ϳ10 Ub-K0 to 16 possible Lys-48 receptor sites on this substrate.…”

Section: Additional Properties Revealed By Elongation Reactions With mentioning

confidence: 94%

A SnapShot of Ubiquitin Chain Elongation

Kovacev

Spratt

et al. 2014

Journal of Biological Chemistry

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Background: Polyubiquitin chains are signaling polypeptides altering the fate of substrates. Results: A Lys-48-ubiquitin chain of a length greater than four, but not its Lys-63 linkage counterparts, slowed the rate of additional ubiquitin conjugation. Conclusion:The ubiquitin chain length and linkage may impact kinetic rates of chain elongation. Significance: Our findings suggest a self-restraining mechanism that limits Lys-48-polyubiquitination.

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Peptidylprolylisomerases, Protein Folders, or Scaffolders? The Example of FKBP51 and FKBP52

Rein

2020

BioEssays

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Peptidylprolyl‐isomerases (PPIases) comprise of the protein families of FK506 binding proteins (FKBPs), cyclophilins, and parvulins. Their common feature is their ability to expedite the transition of peptidylprolyl bonds between the cis and the trans conformation. Thus, it seemed highly plausible that PPIase enzymatic activity is crucial for protein folding. However, this has been difficult to prove over the decades since their discovery. In parallel, more and more studies have discovered scaffolding functions of PPIases. This essay discusses the hypothesis that PPIase enzymatic activity might be the consequence of binding to peptidylprolyl protein motifs. The main focus of this paper is the large immunophilins FKBP51 and FKBP52, but other PPIases such as cyclophilin A and Pin1 are also described. From the hypothesis, it follows that the PPIase activity of these proteins might be less relevant, if at all, than the organization of protein complexes through versatile protein binding. Also see the video abstract here https://youtu.be/A33la0dx5LE.

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The Glomuvenous Malformation Protein Glomulin Binds Rbx1 and Regulates Cullin RING Ligase-Mediated Turnover of Fbw7

Cited by 58 publications

References 44 publications

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

A SnapShot of Ubiquitin Chain Elongation

Peptidylprolylisomerases, Protein Folders, or Scaffolders? The Example of FKBP51 and FKBP52

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