Tight, cell type-specific control of LNX expression in the nervous system, at the level of transcription, translation and protein stability

Lenihan, Joan A.; Saha, Orthis; Mansfield, Louise M.; Young, Paul

doi:10.1016/j.gene.2014.09.011

Cited by 13 publications

(44 citation statements)

References 33 publications

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“…LNX2 protein is detectable at embryonic and early postnatal stages, but decreases dramatically thereafter. Given that Lnx2 mRNA expression persists into adulthood, the downregulation of LNX2 expression seems to be occurring post transcriptionally, possibly at the level of translation as has been described for LNX1 [ 2,11 ], although a high protein turnover rate may also contribute to the low levels of LNX proteins observed in vivo.…”

Section: Discussionmentioning

confidence: 89%

“…We have previously shown that this line, which we refer to as Lnx1 , lacks expression of the neuronally expressed LNX1 p70 and p62 protein isoforms (Fig. 1 c) [ 11 ]. Comprehensive phenotyping of this line, which included some basic neurological and behavioural tests, did not reveal any significant findings apart from an increased percentage of B1like B cells in peritoneal lavage ( https://www.mmrrc.org/catalog/sds.php?mmrrc_id=32436 ).…”

Section: Generation Of Lnx 1/2 Double Knockout Micementioning

confidence: 89%

“…1 a). This is expected to abolish transcription of these neuronal isoforms, but should not affect the expression of the nonneuronal LNX1 p80 isoform that is transcribed from a different upstream promoter [ 11 ].…”

Section: Animalsmentioning

confidence: 99%

“…1 ). The RING domain harbours the catalytic E3 ubiquitin ligase activity, but notably, the shorter LNX1 p70 and p62 isoforms that are expressed in the brain lack the RING domain, suggesting that they might have functions that are independent of ubiquitination [ 1,11 ]. No such alternative splicing of Lnx2 has been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, we need to consider interacting proteins beyond NUMB and NUMBLIKE that may be substrates for ubiquitination by LNX proteins or that may mediate E3 ligaseindependent LNX functions. Given the low and potentially cell typerestricted expression patterns of LNX proteins [ 8,11,17 ], the identification of physiologically relevant interacting proteins and substrates will be key to elucidating the in vivo functions of LNX proteins. neuronal transcripts, is deleted and replaced by a neomycin resistance cassette.…”

Section: Introductionmentioning

confidence: 99%

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Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice

et al. 2016

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Type of publicationArticle (peer-reviewed) AbstractNUMB is a key regulator of neurogenesis and neuronal differentiation that can be ubiquitinated and targeted for proteasomal degradation by ligand of numb proteinX (LNX) family E3 ubiquitin ligases. However, our understanding of LNX protein function in vivo is very limited. To examine the role of LNX proteins in regulating NUMB function in vivo, we generated mice lacking both LNX1 and LNX2 expression in the brain. Surprisingly, these mice are healthy, exhibit unaltered levels of NUMB protein and do not display any neuroanatomical defects indicative of aberrant NUMB function. Behavioural analysis of LNX1/LNX2 double knockout mice revealed decreased anxiety related behaviour, as assessed in the open field and elevated plus maze paradigms. By contrast, no major defects in learning, motor or sensory function were observed. Given the apparent absence of major NUMB dysfunction in LNX null animals, we performed a proteomic analysis to identify neuronal LNXinteracting proteins other than NUMB that might contribute to the anxiolytic phenotype observed. We identified and/or confirmed interactions of LNX1 and LNX2 with proteins known to have presynaptic and neuronal signalling functions, including the presynaptic active zone constituents ERC1, ERC2 and LIPRINαs (PPFIA1, PPFIA3), as well as the FBAR domain proteins FCHSD2 (nervous wreck homologue) and SRGAP2. These and other novel LNXinteracting proteins identified are promising candidates to mediate LNX functions in the central nervous system, including their role in modulating anxietyrelated behaviour.

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Section: Discussionmentioning

confidence: 89%

Section: Generation Of Lnx 1/2 Double Knockout Micementioning

confidence: 89%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice

et al. 2016

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PDZRN4 acts as a suppressor of cell proliferation in human liver cancer cell lines

Yang

Han

2015

Cell Biochemistry & Function

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Recently, some reports show that Ligand of Numb Protein-X 1 (LNX1) could be a suppressor gene in gliomas, while our current research has firstly shown that PDZ domain containing ring finger 4 (PDZRN4), another member of LNX family, could also be a potential suppressor in hepatocellular carcinoma (HCC). PDZRN4, also named LNX4 (Ligand of Numb Protein-X 4), is a member of the LNX family. We recently found that PDZRN4, but not LNX1, was down-regulated in HCC samples, and the role of PDZRN4 in the progression of HCC had not been studied before. To address this question, firstly, we evaluated the expression of PDZRN4 in HCC samples and adjacent non-cancerous tissues. Semi-quantitative polymerase chain reaction showed that PDZRN4 was down-regulated in 24/36 (66.7%) HCC samples separately. In addition, our research shows that PDZRN4 is silenced in all of the 12 HCC cell lines tested. Subsequently, cell-based functional assay exhibited that ectopic expression of PDZRN4 inhibits the proliferation, plate colony formation and anchorage-independent colony formation of HCC cells. Collectively, our results showed that PDZRN4 might be a potential tumour suppressor gene and had anti-proliferative effect on HCC cell proliferation, which would be of great significance to the researches on HCC.

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E3 ubiquitin ligases LNX1 and LNX2 are major regulators of the presynaptic glycine transporter GlyT2

Rocha-Muñoz

Núñez

Arribas-González

et al. 2019

Sci Rep

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The neuronal glycine transporter GlyT2 is an essential regulator of glycinergic neurotransmission that recaptures glycine in presynaptic terminals to facilitate transmitter packaging in synaptic vesicles. Alterations in GlyT2 expression or activity result in lower cytosolic glycine levels, emptying glycinergic synaptic vesicles and impairing neurotransmission. Lack of glycinergic neurotransmission caused by GlyT2 loss-of-function mutations results in Hyperekplexia, a rare neurological disease characterized by generalized stiffness and motor alterations that may cause sudden infant death. Although the importance of GlyT2 in pathology is known, how this transporter is regulated at the molecular level is poorly understood, limiting current therapeutic strategies. Guided by an unbiased screening, we discovered that E3 ubiquitin ligase Ligand of Numb proteins X1/2 (LNX1/2) modulate the ubiquitination status of GlyT2. The N-terminal RING-finger domain of LNX1/2 ubiquitinates a cytoplasmic C-terminal lysine cluster in GlyT2 (K751, K773, K787 and K791), and this process regulates the expression levels and transport activity of GlyT2. The genetic deletion of endogenous LNX2 in spinal cord primary neurons causes an increase in GlyT2 expression and we find that LNX2 is required for PKC-mediated control of GlyT2 transport. This work identifies, to our knowledge, the first E3 ubiquitin-ligases acting on GlyT2, revealing a novel molecular mechanism that controls presynaptic glycine availability. Providing a better understanding of the molecular regulation of GlyT2 may help future investigations into the molecular basis of human disease states caused by dysfunctional glycinergic neurotransmission, such as hyperekplexia and chronic pain.

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Tight, cell type-specific control of LNX expression in the nervous system, at the level of transcription, translation and protein stability

Cited by 13 publications

References 33 publications

Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice

Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice

PDZRN4 acts as a suppressor of cell proliferation in human liver cancer cell lines

E3 ubiquitin ligases LNX1 and LNX2 are major regulators of the presynaptic glycine transporter GlyT2

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