Nuclear export of ubiquitinated proteins via the UBIN-POST system

Hirayama, Shoshiro; Sugihara, Munechika; Morito, Daisuke; Iemura, Shun‐ichiro; Natsume, Tohru; Murata, Shigeo; Nagata, Kazuhiro

doi:10.1073/pnas.1711017115

Cited by 31 publications

(35 citation statements)

References 54 publications

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“…The APEX2 results suggest that UBQLNs may not only deliver proteins to the proteasome to be degraded but also promote proteasome-independent signaling roles of ubiquitin. For more information regarding this experiment, see Supplemental Discussion and Table S4 ( 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ).…”

Section: Resultsmentioning

confidence: 99%

Global proteomics of Ubqln2-based murine models of ALS

Whiteley

Prado

Poot

et al. 2021

Journal of Biological Chemistry

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Familial neurodegenerative diseases commonly involve mutations that result in either aberrant proteins or dysfunctional components of the proteolytic machinery that act on aberrant proteins. UBQLN2 is a ubiquitin receptor of the UBL/UBA family that binds the proteasome through its ubiquitin-like domain and is thought to deliver ubiquitinated proteins to proteasomes for degradation. UBQLN2 mutations result in familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia in humans through an unknown mechanism. Quantitative multiplexed proteomics was used to provide for the first time an unbiased and global analysis of the role of Ubqln2 in controlling the composition of the proteome. We studied several murine models of Ubqln2 -linked ALS and also generated Ubqln2 null mutant mice. We identified impacts of Ubqln2 on diverse physiological pathways, most notably serotonergic signaling. Interestingly, we observed an upregulation of proteasome subunits, suggesting a compensatory response to diminished proteasome output. Among the specific proteins whose abundance is linked to UBQLN2 function, the strongest hits were the ubiquitin ligase TRIM32 and two retroelement-derived proteins, PEG10 and CXX1B. Cycloheximide chase studies using induced human neurons and HEK293 cells suggested that PEG10 and TRIM32 are direct clients. Although UBQLN2 directs the degradation of multiple proteins via the proteasome, it surprisingly conferred strong protection from degradation on the Gag-like protein CXX1B, which is expressed from the same family of retroelement genes as PEG10. In summary, this study charts the proteomic landscape of ALS-related Ubqln2 mutants and identifies candidate client proteins that are altered in vivo in disease models and whose degradation is promoted by UBQLN2.

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Section: Resultsmentioning

confidence: 99%

Global proteomics of Ubqln2-based murine models of ALS

Whiteley

Prado

Poot

et al. 2021

Journal of Biological Chemistry

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“…The search for novel cargos is still on-going, and continues to provide further insight into the physiological relevance of XPO1. For example, it has been recently found that the NES-containing protein POST and the ubiquitin-binding protein UBIN form a complex that mediates XPO1-dependent nuclear export of polyubiquitinated proteins [35] , a process that seems to be exacerbated in cancer cells treated with the proteasome inhibitor bortezomib [36] . These findings reveal a novel role for XPO1 in nuclear protein homeostasis that might also have important implications for cancer therapy.…”

Section: Xpo1-mediated Protein Nuclear Export: Cargos Mechanisms Andmentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…However, proteasomal inhibition or the inability of the proteasome to recognize the substrate would stabilize the polyubiquitinated proteins, thus their transport across the NE could be envisaged. In line with this possibility, the experiments with mammalian cell lines treated with the proteasome inhibitors showed active transport of polyubiquitinated proteins from the nucleus to the cytoplasm by a nuclear export pathway [ 111 ]. In response to proteasome inhibition, K48-linked polyubiquitinated proteins were exported to the cytosol in a CRM1 (exportin-1 [ 112 ]) dependent manner, via interaction of polyubiquitinated proteins with a protein complex consisting of the ubiquitin-binding protein UBIN (UBQLN4, [ 113 ]) and a NES-containing protein termed polyubiquitinated substrate transporter (POST) [ 111 ].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance

2021

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Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.

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Nuclear export of ubiquitinated proteins via the UBIN-POST system

Cited by 31 publications

References 54 publications

Global proteomics of Ubqln2-based murine models of ALS

Global proteomics of Ubqln2-based murine models of ALS

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance

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