scholarly journals A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover

2009 ◽  
Vol 184 (6) ◽  
pp. 881-894 ◽  
Author(s):  
Scott W. Eastman ◽  
Mina Yassaee ◽  
Paul D. Bieniasz
Keyword(s):  
Oleic Acid ◽  
Rna Interference ◽  
Ubiquitin Ligase ◽  
Neurological Disease ◽  
Lipid Droplets ◽  
Adipocyte Differentiation ◽  
Ubiquitin Ligases ◽  
Eukaryotic Cells ◽  
Related Protein ◽  
C Terminus

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.

scholarly journals FIT2 organizes lipid droplet biogenesis with ER tubule-forming proteins and septins

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Fang Chen ◽  
Bing Yan ◽  
Jie Ren ◽  
Rui Lyu ◽  
Yanfang Wu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Oleic Acid ◽  
Energy Metabolism ◽  
Molecular Basis ◽  
Lipid Droplets ◽  
Adipocyte Differentiation ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Cytoskeletal Protein ◽  
Interacting Proteins

Lipid droplets (LDs) are critical for lipid storage and energy metabolism. LDs form in the endoplasmic reticulum (ER). However, the molecular basis for LD biogenesis remains elusive. Here, we show that fat storage–inducing transmembrane protein 2 (FIT2) interacts with ER tubule-forming proteins Rtn4 and REEP5. The association is mainly transmembrane domain based and stimulated by oleic acid. Depletion of ER tubule-forming proteins decreases the number and size of LDs in cells and Caenorhabditis elegans, mimicking loss of FIT2. Through cytosolic loops, FIT2 binds to cytoskeletal protein septin 7, an interaction that is also required for normal LD biogenesis. Depletion of ER tubule-forming proteins or septins delays nascent LD formation. In addition, FIT2-interacting proteins are up-regulated during adipocyte differentiation, and ER tubule-forming proteins, septin 7, and FIT2 are transiently enriched at LD formation sites. Thus, FIT2-mediated nascent LD biogenesis is facilitated by ER tubule-forming proteins and septins.

scholarly journals Ubiquitination and Degradation of Mutant p53

2007 ◽  
Vol 27 (23) ◽  
pp. 8284-8295 ◽  
Author(s):  
Natalia Lukashchuk ◽  
Karen H. Vousden
Keyword(s):  
Tumor Cells ◽  
Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Mutant P53 ◽  
Wild Type ◽  
Independent Manner ◽  
Interacting Protein ◽  
C Terminus ◽  
Wild Type P53 ◽  
Mutant Forms

ABSTRACT While wild-type p53 is normally a rapidly degraded protein, mutant forms of p53 are stabilized and accumulate to high levels in tumor cells. In this study, we show that mutant and wild-type p53 proteins are ubiquitinated and degraded through overlapping but distinct pathways. While Mdm2 can drive the degradation of both mutant and wild-type p53, our data suggest that the ability of Mdm2 to function as a ubiquitin ligase is less important in the degradation of mutant p53, which is heavily ubiquitinated in an Mdm2-independent manner. Our initial attempts to identify ubiquitin ligases that are responsible for the ubiquitination of mutant p53 have suggested a role for the chaperone-associated ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein), although other unidentified ubiquitin ligases also appear to contribute. The contribution of Mdm2 to the degradation of mutant p53 may reflect the ability of Mdm2 to deliver the ubiquitinated mutant p53 to the proteasome.

Role of adipocyte differentiation-related protein in surfactant phospholipid synthesis by type II cells

2002 ◽  
Vol 283 (2) ◽  
pp. L288-L296 ◽  
Author(s):  
C. J. Schultz ◽  
E. Torres ◽  
C. Londos ◽  
J. S. Torday
Keyword(s):  
Lipid Droplets ◽  
Adipocyte Differentiation ◽  
Neutral Lipids ◽  
Lipid Storage ◽  
Alveolar Type ◽  
Mrna Levels ◽  
Type Ii ◽  
Rat Lung ◽  
Related Protein ◽  
Phospholipid Synthesis

Adipocyte differentiation-related protein (ADrP) is an intrinsic lipid storage droplet protein that is highly expressed in lung. ADrP localizes to lipid storage droplets within lipofibroblasts, pulmonary cells characterized by high triacylglycerol, which is a precursor for surfactant phospholipid synthesis by alveolar type II epithelial (EPII) cells. The developmental pattern of ADrP mRNA and protein expression in lung tissue parallels triacylglycerol accumulation in rat lung. ADrP mRNA levels are relatively high in isolated lipofibroblasts, accounting for the high ADrP expression in lung. Isolated EPII cells, which do not store neutral lipids but derive them from lipofibroblasts, have low levels of ADrP mRNA expression. ADrP is found around lipid droplets in cultured lipofibroblasts, but not in EPII cells isolated from developing rat lung. After coculture with lipofibroblasts, EPII cells acquired ADrP, which associates with lipid droplets. Furthermore,3H-labeled triolein in isolated ADrP-coated lipid droplets is a tenfold better substrate for surfactant phospholipid synthesis by cultured EPII cells than 3H-labeled synthetic triolein alone. Antibodies to ADrP block transfer of neutral lipid. These data suggest a role for ADrP in this novel mechanism for the transfer of lipid between lipofibroblasts and EPII cells.

scholarly journals Structure and function of HECT E3 ubiquitin ligases and their role in oxidative stress

2020 ◽  
Vol 8 (2) ◽  
pp. 71-79
Author(s):  
Hao Qian ◽  
Ying Zhang ◽  
Boquan Wu ◽  
Shaojun Wu ◽  
Shilong You ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Vital Role ◽  
E3 Ubiquitin Ligases ◽  
Cellular Environment ◽  
C Terminus ◽  
And Function ◽  
Substrate Proteins

AbstractUbiquitination is a modification after protein transcription that plays a vital role in maintaining the homeostasis of the cellular environment. The Homologous to E6AP C-terminus (HECT) family E3 ubiquitin ligases are a kind of E3 ubiquitin ligases with a C-terminal HECT domain that mediates the binding of ubiquitin to substrate proteins and a variable-length N-terminal extension. HECT-ubiquitinated ligases can be divided into three categories: NEDD4 superfamily, HERC superfamily, and other HECT superfamilies. HECT ubiquitin ligase plays an essential role in the development of many human diseases. In this review, we focus on the physiological and pathological processes involved in oxidative stress and the role of E3 ubiquitin ligase of the HECT family.

scholarly journals A Phospholipase D-dependent Process Forms Lipid Droplets Containing Caveolin, Adipocyte Differentiation-related Protein, and Vimentin in a Cell-free System

2003 ◽  
Vol 278 (29) ◽  
pp. 27293-27300 ◽  
Author(s):  
Denis Marchesan ◽  
Mikael Rutberg ◽  
Linda Andersson ◽  
Lennart Asp ◽  
Thomas Larsson ◽  
...  
Keyword(s):  
Phospholipase D ◽  
Lipid Droplets ◽  
Adipocyte Differentiation ◽  
Related Protein ◽  
Free System ◽  
Cell Free System ◽  
Dependent Process ◽  
A Cell

scholarly journals Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1015
Author(s):  
Utsa Bhaduri ◽  
Giuseppe Merla
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
Genetic Disorders ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Post Translational Modification ◽  
Disease Biology ◽  
The Future

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

scholarly journals TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 820
Author(s):  
Lorena Kumarasinghe ◽  
Lu Xiong ◽  
Maria Adelaida Garcia-Gimeno ◽  
Elisa Lazzari ◽  
Pascual Sanz ◽  
...  
Keyword(s):  
Common Ancestor ◽  
Genetic Diseases ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Lafora Disease ◽  
C Terminus ◽  
Rare Genetic Diseases ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Ring E3

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

scholarly journals Interaction of the Aspergillus nidulans Microtubule-Organizing Center (MTOC) Component ApsB with Gamma-Tubulin and Evidence for a Role of a Subclass of Peroxisomes in the Formation of Septal MTOCs

2010 ◽  
Vol 9 (5) ◽  
pp. 795-805 ◽  
Author(s):  
Nadine Zekert ◽  
Daniel Veith ◽  
Reinhard Fischer
Keyword(s):  
Aspergillus Nidulans ◽  
Protein Complexes ◽  
Spindle Pole ◽  
Eukaryotic Cells ◽  
Microtubule Organizing Center ◽  
Body Protein ◽  
Content Type ◽  
C Terminus ◽  
Peroxisomal Targeting ◽  
Gamma Tubulin

ABSTRACT Peroxisomes are a diverse class of organelles involved in different physiological processes in eukaryotic cells. Although proteins imported into peroxisomes carry a peroxisomal targeting sequence at the C terminus (PTS1) or an alternative one close to the N terminus (PTS2), the protein content of peroxisomes varies drastically. Here we suggest a new class of peroxisomes involved in microtubule (MT) formation. Eukaryotic cells assemble MTs from distinct points in the cell. In the fungus Aspergillus nidulans, septum-associated microtubule-organizing centers (sMTOCs) are very active in addition to the spindle pole bodies (SPBs). Previously, we identified a novel MTOC-associated protein, ApsB (Schizosaccharomyces pombe mto1), whose absence affected MT formation from sMTOCs more than from SPBs, suggesting that the two protein complexes are organized differently. We show here that sMTOCs share at least two further components, gamma-tubulin and GcpC (S. pombe Alp6) with SPBs and found that ApsB interacts with gamma-tubulin. In addition, we discovered that ApsB interacts with the Woronin body protein HexA and is targeted to a subclass of peroxisomes via a PTS2 peroxisomal targeting sequence. The PTS2 motif was necessary for function but could be replaced with a PTS1 motif at the C terminus of ApsB. These results suggest a novel function for a subclass of peroxisomes in cytoskeletal organization.

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