Regulators of the Proteasome Pathway, Uch37 and Rpn13, Play Distinct Roles in Mouse Development

Al-Shami, Amin; Jhaver, Kanchan; Vogel, Peter; Wilkins, Carrie; Humphries, Juliane; Davis, Joseph R.; Xu, Nanfei; Potter, David; Gerhardt, Brenda; Mullinax, Robert A.; Shirley, Cynthia R.; Anderson, Stephen J.; Oravecz, Tamás

doi:10.1371/journal.pone.0013654

Cited by 78 publications

(71 citation statements)

References 44 publications

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“…The majority of 26S proteasomes contain Rpn13, although some do not, and therefore, it remains debatable whether Rpn13 is or is not an integral subunit of the 26S proteasome. The majority of Rpn13-defi cient mice survived to adulthood, although they were smaller at birth and fewer in number than wild-type littermates (Al -Shami et al, 2010 ). Absence of Rpn13 produced tissue-specifi c effects on proteasomal function: increased proteasome activity in adrenal glands and lymphoid organs and decreased activity in the testes and brain.…”

Section: Ubiquitin Receptor Proteasomal Receptors That Recognizementioning

confidence: 99%

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The proteasome: molecular machinery and pathophysiological roles

Tanaka

Mizushima

Saeki

2012

BCHM

108

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The 26S proteasome, in collaboration with ubiquitin, operates the energy-dependent regulated proteolysis process in eukaryotic cells. Over the past 30 years, several studies have comprehensively characterized the structure and molecular/ physiological functions of the 26S proteasome. It is a sophisticated 2.5-MDa protein degradation machine comprising a proteolytic core particle (CP) and one or two terminal regulatory particle(s) (RP). The CP consists of two outer α rings and two inner β rings, which are made up of seven structurally similar α and β subunits, respectively. The CP contains catalytic threonine residues ( β 1, β 2, and β 5; caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the inner surface of the chamber formed by two abutting β rings. Intriguingly, the immunotype proteasomes, named ' immunoproteasome ' and ' thymoproteasome ' , whose catalytic subunits are replaced by the related counterparts, were discovered lately. Both unique isoenzymes essentially contribute to the acquisition of adaptive immunity in vertebrates. The RP, which serves to recognize polyubiquitylated substrate proteins and plays a role in their deubiquitylating, unfolding, and translocation into the interior of the CP for destruction, forms two subcomplexes: the base and the lid. On another front, the PA28 and PA200, alternative CP activator proteins discovered biochemically, both play independent roles in proteolysis of the 26S proteasome. Several studies have highlighted the importance of the proteasome in various intractable diseases that have been increasing in the aged society of the 21st century.

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Section: Ubiquitin Receptor Proteasomal Receptors That Recognizementioning

confidence: 99%

“…Intriguingly, deletion of Uch37 resulted in prenatal lethality in mice associated with severe defect in embryonic brain development, suggesting that Uch37 and Rpn13 play distinct roles in mouse development (Al -Shami et al, 2010 ), though Uch37 is associated with Rpn13.…”

Section: Deubiquitylating Enzymesmentioning

confidence: 99%

The proteasome: molecular machinery and pathophysiological roles

Tanaka

Mizushima

Saeki

2012

BCHM

108

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“…We generated Itfg2-null mice by gene trapping as previously described (20,21). The Lexicon OmniBank embryonic stem cell (ESC) clone OST215121 was selected for microinjection based on sequence similarity to the mouse Itfg2 gene (GenBank accession no.…”

Section: Generation Of Itfg2 Mutant Micementioning

confidence: 99%

“…RT-PCR was performed as described previously (21), using oligonucleotide primers complementary to exons 1 and 4 of Itfg2 (59-CCA GAG TGC CAT GAG GTC GGT TAG TTA TG-39 and 59-GTG GGT GTC AGG TCA AAC AAG TGC-39). To evaluate whether disruption of Itfg2 affected expression of the neighboring FK506 binding protein 4 (Fkbp4) gene (GenBank accession number NM_010219), we also analyzed the same RNA samples using the Fkbp4-specific primers 59-GTGAATGACTTT-GACCTGGCAAGAGC-39 and 59-CATTGTTCCGCTCACCCTTCATCT-CAGC-39.…”

Section: Gene Expression Analysis By Rt-pcrmentioning

confidence: 99%

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Integrin-α FG-GAP Repeat-Containing Protein 2 Is Critical for Normal B Cell Differentiation and Controls Disease Development in a Lupus Model

Al-Shami

Crisostomo

Wilkins

et al. 2013

The Journal of Immunology

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The phenylalanyl-glycyl–glycyl-alanyl-prolyl (FG-GAP) domain plays an important role in protein–protein interactions, including interaction of integrins with their ligands. Integrin-α FG-GAP repeat-containing protein 2 (Itfg2) is a highly conserved protein in vertebrates that carries two FG-GAP domains, but its role in mammalian physiology is unknown. In this article, we show that Itfg2 is an intracellular protein and it plays a critical role in B cell differentiation and development of autoimmunity. Itfg2-deficient mice displayed a phenotype consistent with retention of B cells in the spleen and had a lower concentration of IgG in the blood when compared with wild-type littermates. Itfg2-deficient splenocytes also showed a defect in cell migration in vitro. After immunization with a thymus-dependent Ag, the absence of Itfg2 caused a shift in B cell maturation from the germinal centers to the extrafollicular regions of the spleen and blocked deposition of Ag-specific plasma cells in the bone marrow. In support of hematopoietic cell intrinsic activity of Itfg2, bone marrow transplantation of Itfg2-deficient cells was sufficient to impair germinal center development in wild-type mice. Furthermore, Itfg2 deficiency exacerbated development of autoimmune disease in MRL/lpr lupus-prone mice. These results identify Itfg2 as a novel contributor to B cell differentiation and a negative regulator of the autoimmune response during lupus.

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Small‐Molecule Inhibitors of the Proteasome's Regulatory Particle

2019

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Cells need to synthesize and degrade proteins consistently. Maintaining a balanced level of protein in the cell requires a carefully controlled system and significant energy. Degradation of unwanted or damaged proteins into smaller peptide units can be accomplished by the proteasome. The proteasome is composed of two main subunits. The first is the core particle (20S CP), and within this core particle are three types of threonine proteases. The second is the regulatory complex (19S RP), which has a myriad of activities including recognizing proteins marked for degradation and shuttling the protein into the 20S CP to be degraded. Small‐molecule inhibitors of the 20S CP have been developed and are exceptional treatments for multiple myeloma (MM). 20S CP inhibitors disrupt the protein balance, leading to cellular stress and eventually to cell death. Unfortunately, the 20S CP inhibitors currently available have dose‐limiting off‐target effects and resistance can be acquired rapidly. Herein, we discuss small molecules that have been discovered to interact with the 19S RP subunit or with a protein closely associated with 19S RP activity. These molecules still elicit their toxicity by preventing the proteasome from degrading proteins, but do so through different mechanisms of action.

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Regulators of the Proteasome Pathway, Uch37 and Rpn13, Play Distinct Roles in Mouse Development

Cited by 78 publications

References 44 publications

The proteasome: molecular machinery and pathophysiological roles

The proteasome: molecular machinery and pathophysiological roles

Integrin-α FG-GAP Repeat-Containing Protein 2 Is Critical for Normal B Cell Differentiation and Controls Disease Development in a Lupus Model

Small‐Molecule Inhibitors of the Proteasome's Regulatory Particle

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