Adrm1, a Putative Cell Adhesion Regulating Protein, is a Novel Proteasome-associated Factor

Jørgensen, Jakob Ploug; Lauridsen, Anne-Marie B.; Kristensen, Poul; Dissing, Karen; Johnsen, Anders H.; Hendil, Klavs B.; Hartmann‐Petersen, Rasmus

doi:10.1016/j.jmb.2006.06.011

Cited by 57 publications

(66 citation statements)

References 40 publications

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“…There were no significant differences in bulk protein degradation caused by Rpn13 knockdown. These results are consistent with prior studies (7,8,10) and suggest that Rpn13 is mostly required for degradation of specific substrates such as iNOS and IκB-α. Some proteins become degraded when bound to proteasomes (26).…”

Section: Resultssupporting

confidence: 93%

“…Based on these findings, the function of ADRM1 as an adhesion molecule is now doubted and, hence, the name is rather a misnomer. Deletion of ADRM1 by siRNA does not lead to global accumulation of ubiquitinated cellular proteins or changes in proteasome expression, suggesting that ADRM1 must have a specialized role in proteasome function (8). Shorty after the above report, three independent groups confirmed that ADRM1 is a novel 19S proteasome cap-associated protein, but they further revealed a unique role for ADRM1 in protein degradation (7,9,10).…”

mentioning

confidence: 89%

“…One such protein is adhesion regulating molecule (ADRM1), which is recently identified as a novel proteasome-associated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome (7)(8)(9)(10). Before this discovery, ADRM1 had been described as a heavily glycosylated membrane protein, which regulates cell adhesion (11).…”

mentioning

confidence: 99%

“…However, in 2006, Jørgensen et al (8) showed that ADRM1 is associated with the 19S regulatory cap. ADRM1 is expressed constitutively and in a nonglycosylated form in almost all tissues.…”

mentioning

confidence: 99%

“…Although Rpn13 is a receptor for ubiquitin (15,16), three of the four groups (7,8,10) found that knockdown of Rpn13 does not affect general short-lived protein degradation, whereas one group observed a slight but consistent reduction (9). These studies, taken toAuthor contributions: T.M., F.M.G., Y.S., S.Z., R.H.-P., J.P.J., K.B.H., and N.T.E.…”

mentioning

confidence: 99%

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Regulation of NF-κB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

Mazumdar

Gorgun

Sha

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Human Rpn13, also known as adhesion regulating molecule 1 (ADRM1), was recently identified as a novel 19S proteasome capassociated protein, which recruits the deubiquitinating enzyme UCH37 to the 26S proteasome. Knockdown of Rpn13 by siRNA does not lead to global accumulation of ubiquitinated cellular proteins or changes in proteasome expression, suggesting that Rpn13 must have a specialized role in proteasome function. Thus, Rpn13 participation in protein degradation, by recruiting UCH37, is rather selective to specific proteins whose degradation critically depends on UCH37 deubiquitination activity. The specific substrates for the Rpn13/UCH37 complex have not been determined. Because of a previous discovery of an interaction between Rpn13 and inducible nitric oxide synthase (iNOS), we hypothesized that iNOS is one of the substrates for the Rpn13/ UCH37 complex. In this study, we show that Rpn13 is involved in iNOS degradation and is required for iNOS interaction with the deubiquitination protein UCH37. Furthermore, we discovered that IκB-α, a protein whose proteasomal degradation activates the transcription factor NF-κB, is also a substrate for the Rpn13/UCH37 complex. Thus, this study defines two substrates, with important roles in inflammation and host defense for the Rpn13/UCH37 pathway.

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Section: Resultssupporting

confidence: 93%

mentioning

confidence: 89%

mentioning

confidence: 99%

“…However, in 2006, Jørgensen et al (8) showed that ADRM1 is associated with the 19S regulatory cap. ADRM1 is expressed constitutively and in a nonglycosylated form in almost all tissues.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Regulation of NF-κB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

Mazumdar

Gorgun

Sha

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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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The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity

Huang

Her

2016

Mol Neurobiol

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an N-terminal expansion of polyglutamine stretch (polyQ) of huntingtin (Htt) protein. HAP40 is a huntingtin-associated protein with unknown cellular functions. Increased HAP40 expression has been reported in the brain of HD patients and HD mouse model. However, the relationship between the elevation of HAP40 and HD etiology remains elusive. In this study, we demonstrated that overexpression of HAP40 enhanced accumulation of mutant Htt aggregates and caused defects in proteasome function. Specifically, excess HAP40 interfered with adhesion-regulating molecule 1 (ADRM1), a proteasome ubiquitin receptor, to regulate the proteasome-dependent pathway. Increasing ADRM1 in the presence of excess HAP40 alleviated mutant Htt aggregates and at the same time, restored the cell viability. Reducing ADRM1 in the absence of excess HAP40; on the other hand, increased mutant Htt aggregates and decreased the cell viability. Our data provide compelling evidence to support that ADRM1 plays an important role in mediating removal of mutant Htt aggregates when excess HAP40 is present. ADRM1-dependent ubiquitin proteasome system (UPS) may be a general mechanism to guard cells from mutant Htt toxicity.

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Adrm1, a Putative Cell Adhesion Regulating Protein, is a Novel Proteasome-associated Factor

Cited by 57 publications

References 40 publications

Regulation of NF-κB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

Regulation of NF-κB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13)

Small‐Molecule Inhibitors of the Proteasome's Regulatory Particle

The Ubiquitin Receptor ADRM1 Modulates HAP40-Induced Proteasome Activity

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