The Ufm1 Cascade

Daniel, Jens; Liebau, Eva

doi:10.3390/cells3020627

Cited by 84 publications

(82 citation statements)

References 39 publications

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“…On the contrary, the efflux of accumulated cholesterol in macrophages is mediated by the cholesterol reverse transporter family, including SR-BI, ABCA1, and ABCG1 41,42) . Therefore, we delineated the mechanism of UFM1 to attenuate lipid accumulation by examining the alterations results are consistent with a previous report that UFM1 is expressed in various tissues and cell lines and that UFM1 is linked with the acti vation of the ER stress response in atherosclerosis, ischemic heart injury, and T2D 21,48,49) . Taken together, our findings strongly indicate that UFM1 is upregulated in ma crophages under atherosclerotic conditions, both in vivo and in vitro and that UFM1 may be a potential therapeutic target for atherosclerosis.…”

Section: Ufm1 Upregulates Abca1 and Abcg1 Expression But Not Class A supporting

confidence: 59%

“…These data indicate diverse functions of UFM1 depending on the function of the target protein. At present, there are increasing evidences, which show that UFM1 is upregulated in pathological conditions that are associated with the activation of the ER stress response, such as type diabetes, ischemic heart injury, and cardiovascular diseases [20][21][22] . Moreover, ER stress is a key regulator of macrophage differentiation and cholesterol deposition in the development of atherosclerosis 23) .…”

Section: Introductionmentioning

confidence: 99%

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UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

JAT

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Aim: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. Methods: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE / mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. Results: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor (LXR ) activation, which was confirmed by the observation that LXR siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. Conclusions: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXR -dependent pathway.

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Section: Ufm1 Upregulates Abca1 and Abcg1 Expression But Not Class A supporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Pang

Xiong

et al. 2015

JAT

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“…41 Although the precise function has not been elucidated yet, the UFM1 cascade seems to be involved in cellular homeostasis, influencing cell division, growth and endoplasmatic reticulum function. 42 UFM1 is highly expressed in the pancreatic islets of Langerhans and has a role in the development of type 2 diabetes. Another study showed possible involvement in the development of ischemic heart disease.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

et al. 2015

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Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10 − 8 and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10 − 10 ), 9q34 (2.4 × 10 − 64 ), 12p13 (5.3 × 10 − 22 ), 12q23 (1.2 × 10 − 8 ) and 13q13 (2.6 × 10 − 8 ). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.

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“…The conjugation and deconjugation of target proteins by Ubls modulates their function and thereby the regulation of cellular processes. [10] In the Ufm1 modification pathway, Ufm1 is activated by either UFSP1 or UFSP2 to expose a C-terminal glycine residue. [7] Activated Ufm1 then reacts with Uba5 (E1-like enzyme) and is transferred to Ufc1 (E2-like enzyme) before being transferred to its target protein by Ufl1 (E3-like enzyme).…”

Section: Discussionmentioning

confidence: 99%

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

et al. 2015

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Background. Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35. Objective. To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing. Results. The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single-candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (θ = 0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1. Conclusion. We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family.

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The Ufm1 Cascade

Cited by 84 publications

References 39 publications

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor α Dependent Pathway

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

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