Seipin: A mysterious protein
Division of Nutrition and Metabolic Diseases, the Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. Trends in Molecular Medicine
(Impact Factor: 9.45).
10/2004; 10(9):440-4. DOI: 10.1016/j.molmed.2004.07.009
In 2001, a locus for autosomal-recessive congenital generalized lipodystrophy was identified on chromosome 11q13 and mutations in a novel gene named Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) were reported. Earlier this year, heterozygous mutations in the BSCL2 gene, restricted to the N-glycosylation (N-X-S/T) motif, were reported in autosomal-dominant distal hereditary motor neuropathy and Silver syndrome, which are disorders with distinctly different phenotypes from lipodystrophy. BSCL2 encodes seipin, a transmembrane protein that is localized to the endoplasmic reticulum. It is proposed that its homology to midasin, an AAA (ATPases associated with various cellular activities) domain-containing nuclear protein that is involved in RNA transport, might yield some clues as to how mutant forms of seipin cause two clinically distinct syndromes.
Available from: Shunhui Wei
- "Abbreviations used: AMPA, a-Amino-3-hydroxy-5-methyl-4-isoxaz- olepropionic acid; dHMN-V, distal hereditary motor neuropathy type V; EPSC, miniature excitatory post-synaptic currents; mIPSC, miniature inhibitory post-synaptic currents; PBS, phosphate-buffered saline; PPR, paired-pulse ratio; RRP, readily releasable pool. truncated, non-functional proteins (Agarwal and Garg 2004; Miranda et al. 2009; Qiu et al. 2013; Yang et al. 2013). "
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ABSTRACT: Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by overexpressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that overexpressed Seipin is partly co-localized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency but not the amplitudes of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). The amplitude of both evoked EPSC and IPSC are also compromised by mutant Seipin overexpression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons overexpressing Seipin-N88S, while neither γ-amino butyric acid (GABA) nor α-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. This article is protected by copyright. All rights reserved.
Journal of Neurochemistry 12/2013; 129(2). DOI:10.1111/jnc.12638 · 4.28 Impact Factor
Available from: Alexander Shekhtman
- "Impaired lipid droplet metabolism might be one of the mechanisms in the pathogenesis of Troyer syndrome. Malfunction of proteins involved in lipid maintenance is considered to be a cause of some neurological disorders . For example, an autosomal-dominant hereditary spastic paraplegia, HSP17, which is characterized by muscle weakness in upper limbs and spasticity of lower limbs, is caused by a mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene encoding seipin . "
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ABSTRACT: Spartin protein is involved in degradation of epidermal growth factor receptor and turnover of lipid droplets and a lack of expression of this protein is responsible for hereditary spastic paraplegia type 20 (SPG20). Spartin is a multifunctional protein that associates with many cellular organelles, including lipid droplets. Recent studies showed that spartin interacts with E3 ubiquitin ligases that belong to the neural precursor cell-expressed developmentally downregulated gene (Nedd4) family, including atrophin-1-interacting protein 4 (AIP4/ITCH). However, the biological importance of the spartin-AIP4 interaction remains unknown.
In this study, we show that spartin is not a substrate for AIP4 activity and that spartin's binding to AIP4 significantly increases self-ubiquitination of this E3 ligase, indicating that spartin disrupts the AIP4 autoinhibitory intramolecular interaction. Correspondingly, spartin has a seven times higher binding affinity to the WW region of AIP4 than the binding of the WW region has to the catalytic homologues of the E6-associated protein C-terminus (HECT) domain, as measured by enzyme-linked immunosorbent assay. We also show that spartin recruits AIP4 to lipid droplets and promotes ubiquitination of lipid droplet-associated protein, adipophilin, which regulates turnover of lipid droplets.
Our findings demonstrate that spartin acts as an adaptor protein that activates and recruits AIP4 E3 ubiquitin ligase to lipid droplets and by this means regulates the level of ubiquitination of adipophilin and potentially other lipid-associated proteins. We propose that this is one of the mechanisms by which spartin regulates lipid droplet turnover and might contribute to the pathology of SPG20.
BMC Biology 05/2010; 8(1):72. DOI:10.1186/1741-7007-8-72 · 7.98 Impact Factor
Available from: Scott W. Eastman
- "NTE is a phospholipase and is a member of the superfamily of patatin domain lipases that also includes the closely related lysophospholipase NTE-related esterase that is found on LDs and adipose triglyceride lipase, which can regulate LD size in nonadipocyte cells (Smirnova et al., 2006; Kienesberger et al., 2008). Additionally, mutation of another human protein, Seipin (BSCL2), has also been shown to be associated with motor neuron disorders, including wasting of distal limb muscles and lower limb spasticity (Agarwal and Garg, 2004; Ito and Suzuki, 2007). Interestingly, yeast lacking a functional homologue of Seipin (FLD1) contain increased levels of neutral lipids and possess irregularly clustered/fused and enlarged LDs, a defect that can be rescued by introduction of human or mouse Seipin (Szymanski et al., 2007; Fei et al., 2008). "
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ABSTRACT: HECT (homologous to the E6AP C terminus) ubiquitin ligases have diverse functions in eukaryotic cells. In screens for proteins that bind to the HECT ubiquitin ligase WWP1, we identified Spartin, which is also known as SPG20. This protein is truncated in a neurological disease, Troyer syndrome. In this study, we show that SPG20 associates with the surface of lipid droplets (LDs) and can regulate their size and number. SPG20 binds to another LD protein, TIP47, and both proteins compete with an additional LD protein, adipophilin/adipocyte differentiation-related protein, for occupancy of LDs. The mutant SPG20 present in Troyer syndrome does not possess these activities. Depletion of SPG20 using RNA interference increases the number and size of LDs when cells are fed with oleic acid. Binding of WWP1 to SPG20 and the consequent ubiquitin transfer remove SPG20 from LDs and reduce the levels of coexpressed SPG20. These experiments suggest functions for ubiquitin ligases and SPG20 in the regulation of LD turnover and potential pathological mechanisms in Troyer syndrome.
The Journal of Cell Biology 04/2009; 184(6):881-94. DOI:10.1083/jcb.200808041 · 9.83 Impact Factor
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