Rpn10-Mediated Degradation of Ubiquitinated Proteins Is Essential for Mouse Development

Hamazaki, Jun; Sasaki, Katsuhiro; Kawahara, Hiroyuki; Hisanaga, Shin‐ichi; Tanaka, Keiji; Murata, Shigeo

doi:10.1128/mcb.00509-07

Cited by 99 publications

(96 citation statements)

References 51 publications

(74 reference statements)

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“…The reconstitution of Rpn10-deficient yeast with human Rpn10 encouraged us to test whether FAT10 degradation could be reconstituted in yeast. The reconstitution of FAT10 degradation in yeast seemed justified as Rpn10 has been shown to be essential in mouse cells 40 and is required for normal degradation of ubiquitin-conjugates in Drosophila 39 . We could show that FAT10 is degraded in yeast in a Rpn10-dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Consistently, mice bearing only a VWA domain survive longer than mice that completely lack mRpn10 (ref. 40). The knockdown of hRpn10 in human HEK293 cells led to an accumulation of FLAG-FAT10 and endogenous FAT10 and bulk FAT10 conjugates (when normalized to the level of FAT10 mRNA), and the UBE1-FAT10 conjugate by 30-50% (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Contrary to yeast, mammalian cells deficient in hRpn10 are not viable over extended periods of time 39,40 . Therefore, the function of hRpn10 in the degradation of FAT10 and its conjugates in mammalian cells was addressed by transiently knocking down hRpn10 with short interfering RNA (siRNA) in HEK293 cells that lead to extensive depletion of hRpn10 (Fig.…”

Section: Hrpn10 Knockdown In Human Cells Causes Fat10 Accumulationmentioning

confidence: 99%

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FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis

et al. 2012

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FAT10 is the only ubiquitin-like modifier that can target proteins for degradation by the proteasome in a ubiquitin-independent manner. The degradation of FAT10-linked proteins by the proteasome is strongly accelerated by the ubiquitin-like-ubiquitin-associated protein nEDD8 ultimate buster-1 long (nuB1L). Here we show how FAT10 and nuB1L dock with the 26s proteasome to initiate proteolysis. We identify the 26s proteasome subunit hRpn10/s5a as the receptor for FAT10, whereas nuB1L can bind to both Rpn10 and Rpn1/s2. unexpectedly, FAT10 and nuB1L both interact with hRpn10 via the VWA domain. FAT10 degradation in yeast shows that human Rpn10 can functionally reconstitute Rpn10-deficient yeast and that the VWA domain of hRpn10 suffices to enable FAT10 degradation. Depletion of hRpn10 causes an accumulation of FAT10-conjugates also in human cells. In conclusion, we identify the VWA domain of hRpn10 as a receptor for ubiquitin-like proteins within the 26s proteasome and elucidate how FAT10 mediates efficient proteolysis by the proteasome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hrpn10 Knockdown In Human Cells Causes Fat10 Accumulationmentioning

confidence: 99%

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FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis

et al. 2012

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“…Another possibility for Cd-induced FGR related to UPS disruption may involve the disruption of important proteins that maintain fetal growth. In fact, excessive polyubiquitinated protein accumulation followed by disruption of UPS leads fetal death in Rpn10 (19S proteasome subunit) mutant mice (Hamazaki et al, 2007). Therefore, disruption of UPS, such as overaccumulation of ubiquitinated proteins and decrease of monoubiquitin level, may be one of the critical mechanisms of Cd-induced FGR.…”

Section: Resultsmentioning

confidence: 99%

Effect of gestational cadmium exposure on fetal growth, polyubiquitinated protein and monoubiqutin levels in the fetal liver of mice

et al. 2018

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-Cadmium (Cd) is an environmental pollutant present in contaminated water, food and soil. Cd adversely affects fetal development. We exposed pregnant mice to daily oral doses of 5 and 10 mg/kg Cd and examined fetal growth. It was demonstrated that the exposure to Cd (10 mg/kg) during gestation caused fetal growth retardation (FGR). Investigation of the ubiquitin-proteasome system in fetal livers of mice exposed to gestational Cd revealed increased polyubiquitinated protein accumulation, contrasting with decreased levels of monoubiquitin protein. Moreover, the expression level of Ubc (encoding polyubiquitin C protein) was significantly decreased in 5 and 10 mg/kg Cd-treated groups in comparison with the control group. Therefore, we propose that decrease of monoubiquitin level and accumulation of polyubiquitinated protein in the fetal liver may be important factors in Cd-induced FGR.

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“…In particular, the importance of Rpn10 in Ub-mediated proteolysis is debatable, as Rpn10 defi ciency results in different phenotypes in different organisms. Surprisingly, Rpn10 knockout mice showed early embryonic lethality, demonstrating the essential role of Rpn10 in mouse development (Hamazaki et al , 2007 ). Rpn10a knock-in mice exclusively expressed the constitutive type of Rpn10, but did not express other vertebrate-specifi c variants and grew normally, indicating that Rpn10 diversity is not essential for conventional development.…”

Section: Ubiquitin Receptor Proteasomal Receptors That Recognizementioning

confidence: 99%

The proteasome: molecular machinery and pathophysiological roles

Tanaka

Mizushima

Saeki

2012

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110

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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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Rpn10-Mediated Degradation of Ubiquitinated Proteins Is Essential for Mouse Development

Cited by 99 publications

References 51 publications

FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis

FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis

Effect of gestational cadmium exposure on fetal growth, polyubiquitinated protein and monoubiqutin levels in the fetal liver of mice

The proteasome: molecular machinery and pathophysiological roles

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