Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleocytoplasmic shuttling

Jiao, Baowei; Taniguchi-Ishigaki, Naoko; Güngör, Cenap; Peters, Marvin; Lin, Chen‐Yong; Drung, Alexander; Ahronian, Leanne G.; Shin, Jongdae; Pagnis, Rachna; Pantel, Klaus; Tachibana, Taro; Lewis, Brian C.; Johnsen, Steven A.; Bach, Ingolf

doi:10.1091/mbc.e13-05-0239

Cited by 29 publications

(39 citation statements)

References 41 publications

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“…ICC on undifferentiated Rlim 340f ESCs revealed predominantly nuclear localization of the truncated RLIM protein (Fig. S2C), consistent with findings that RLIM lacking the NES is trapped in the nucleus (Jiao et al, 2013). Moreover, forced expression of Myc-tagged RLIM340 in Rlim KOp ESCs via transient transfections revealed accumulation of endogenous REX1 protein in nuclei of transfected cells (Fig.…”

Section: Resultssupporting

confidence: 86%

“…The X-linked gene Rlim (also known as Rnf12 ) has emerged as a critical mediator of Xist activity. Rlim encodes a ubiquitin ligase (E3) (Ostendorff et al, 2002) that is involved in transcriptional regulation (Bach et al, 1999; Gontan et al, 2012; Gungor et al, 2007) and shuttles between the nucleus and cytoplasm (Jiao et al, 2013). In mice, a maternally transmitted Rlim KO allele ( m) results in early lethality of female embryos in a sex-specific parent-of-origin effect due to a failure to maintain iXCI and Xist clouds (Shin et al, 2010; Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Rlim -Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

et al. 2017

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SUMMARY During female mouse embryogenesis, two forms of X chromosome inactivation (XCI) ensure dosage compensation from sex chromosomes. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp), and this pattern is maintained in extraembryonic cell types. Epiblast cells, which give rise to the embryo proper, reactivate the Xp (XCR) and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI is dependent on the long non-coding RNA Xist. The ubiquitin ligase RLIM is required for iXCI in vivo and occupies a central role in current models of rXCI. Here, we demonstrate the existence of Rlim-dependent and -independent pathways for rXCI in differentiating female ESCs. Upon uncoupling these pathways we find more efficient Rlim-independent XCI in ESCs cultured under physiological oxygen conditions. Our results revise current models of rXCI and suggest that caution must be taken when comparing XCI studies in ESCs and mice.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Rlim -Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

et al. 2017

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“…It affects cell migration by ubiquitinating the negative regulator Smad7 [11] and through its direct binding to the E3 ubiquitin-protein ligase SMURF2 [21]. Furthermore, RLIM affects expression of estrogen responsive genes through ubiquitination [22] and phosphorylation [23] of estrogen receptor alpha [6,12,22,23] and hereby regulates its biological activity together with its cofactor CLIM in primary breast cancer tumor cells [22]. RLIM is a critical survival factor for mammary gland milk-producing alveolar cells [22].…”

Section: Introductionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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Section: Discussionmentioning

confidence: 99%

“…11 It is crucial for normal embryonic development in some species 12 and for normal X inactivation in mice. 9,13 RNF12 mainly localizes to the cell nucleus, 11 where it regulates the levels of many proteins, including CLIM, LMO, HDAC2, TRF1, SMAD7 and REX1, by proteasomal degradation. 7,9,12,14 Thus, it modulates the activity of transcription factors, in particular those containing a LIM homeodomain, 15 and the formation of transcriptional multiprotein complexes.…”

Section: Discussionmentioning

confidence: 99%

Syndromic X-linked intellectual disability segregating with a missense variant in RLIM

et al. 2015

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We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A4G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.

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Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleocytoplasmic shuttling

Cited by 29 publications

References 41 publications

Rlim -Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

Rlim -Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Syndromic X-linked intellectual disability segregating with a missense variant in RLIM

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