MeCP2 ubiquitination and sumoylation, in search of a function

Kalani, Ladan; Kim, Bo-Hyun; Vincent, John B; Ausió, Juan

doi:10.1093/hmg/ddad150

Cited by 3 publications

(1 citation statement)

References 143 publications

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“…DeSUMOylation of RIPK1 mediated by SENP1 has also been shown to inhibit the activation of RIPK1 kinase in promoting apoptosis and inflammation ( 54 ). Ubiquitination and sumoylation have been shown in regulating Mecp2 activity which may have consequences on the potential functional outcomes in RTT ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT

Cao,

Min,

Xie

et al. 2024

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

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Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

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Section: Discussionmentioning

confidence: 99%

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT

Cao,

Min,

Xie

et al. 2024

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

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Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms

Kalani,

Kim,

de Chavez

et al. 2024

Human Molecular Genetics

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Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

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USP15 inhibits hypoxia‐induced IL‐6 signaling by deubiquitinating and stabilizing MeCP2

Zhang,

Niu,

et al. 2024

The FEBS Journal

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Methyl‐CpG binding protein 2 (MeCP2) is an important X‐linked DNA methylation reader and a key heterochromatin organizer. The expression level of MeCP2 is crucial, as indicated by the observation that loss‐of‐function mutations of MECP2 cause Rett syndrome, whereas an extra copy spanning the MECP2 locus results in MECP2 duplication syndrome, both being progressive neurodevelopmental disorders. Our previous study demonstrated that MeCP2 protein expression is rapidly induced by renal ischemia–reperfusion injury (IRI) and protects the kidney from IRI through transcriptionally repressing the interleukin‐6 (IL‐6)/signal transducer and activator of transcription 3 signaling pathway. However, the mechanisms underlying the upregulation of MeCP2 have remained elusive. Here, by using two hypoxia cell models, hypoxia and reoxygenation and cobalt chloride stimulation, we confirmed that the removal of lysine 48‐linked ubiquitination from MeCP2 prevented its proteasome‐dependent degradation under hypoxic conditions. Through unbiased screening based on a deubiquitinating enzymes library, we identified ubiquitin‐specific protease 15 (USP15) as a stabilizer of MeCP2. Further studies revealed that USP15 could attenuate hypoxia‐induced MeCP2 degradation by cleaving lysine 48‐linked ubiquitin chains from MeCP2, primarily targeting its C‐terminal domain. Consistently, USP15 inhibited hypoxia‐induced signal transducer and activator of transcription 3 activation, resulting in reduced transcription of IL‐6 downstream genes. In summary, our study reveals an important role for USP15 in the maintenance of MeCP2 stability and the regulation of IL‐6 signaling.

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MeCP2 ubiquitination and sumoylation, in search of a function

Cited by 3 publications

References 143 publications

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT

Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms

USP15 inhibits hypoxia‐induced IL‐6 signaling by deubiquitinating and stabilizing MeCP2

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