hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50

doi:10.1016/j.molcel.2023.11.035

. 2024 Feb 1;84(3):522-537.e8.

doi: 10.1016/j.molcel.2023.11.035. Epub 2023 Dec 26.

hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50

Affiliations

¹ Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
² Optical Microscopy and Image Analysis Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
³ Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA.
⁴ Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
⁵ Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Sequencing Facility, Cancer Research and Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
⁷ Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
⁸ Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁹ Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address: kylie.walters@nih.gov.

PMID: 38151017
PMCID: PMC10872465 (available on 2025-02-01)
DOI: 10.1016/j.molcel.2023.11.035

hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50

Vasty Osei-Amponsa et al. Mol Cell. 2024.

. 2024 Feb 1;84(3):522-537.e8.

doi: 10.1016/j.molcel.2023.11.035. Epub 2023 Dec 26.

Authors

Affiliations

¹ Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
² Optical Microscopy and Image Analysis Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
³ Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA.
⁴ Biophysics Resource, Center for Structural Biology, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
⁵ Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Sequencing Facility, Cancer Research and Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
⁷ Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
⁸ Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁹ Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address: kylie.walters@nih.gov.

PMID: 38151017
PMCID: PMC10872465 (available on 2025-02-01)
DOI: 10.1016/j.molcel.2023.11.035

Abstract

The anti-cancer target hRpn13 is a proteasome substrate receptor. However, hRpn13-targeting molecules do not impair its interaction with proteasomes or ubiquitin, suggesting other critical cellular activities. We find that hRpn13 depletion causes correlated proteomic and transcriptomic changes, with pronounced effects in myeloma cells for cytoskeletal and immune response proteins and bone-marrow-specific arginine deiminase PADI4. Moreover, a PROTAC against hRpn13 co-depletes PADI4, histone deacetylase HDAC8, and DNA methyltransferase MGMT. PADI4 binds and citrullinates hRpn13 and proteasomes, and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. When off proteasomes, hRpn13 can bind HDAC8, and this interaction inhibits HDAC8 activity. Further linking hRpn13 to transcription, its loss reduces nuclear factor κB (NF-κB) transcription factor p50, which proteasomes generate by cleaving its precursor protein. NF-κB inhibition depletes hRpn13 interactors PADI4 and HDAC8. Altogether, we find that hRpn13 acts dually in protein degradation and expression and that proteasome constituency and, in turn, regulation varies by cell type.

Keywords: HDAC8; MGMT; MYH10; NF-κB; PADI4; citrulline; cytoskeleton; gene regulation; hRpn13; proteasome.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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References

1. Osei-Amponsa V, and Walters KJ (2022). Proteasome substrate receptors and their therapeutic potential. Trends Biochem Sci 47, 950–964. 10.1016/j.tibs.2022.06.006. - DOI - PMC - PubMed
1. Song Y, Ray A, Li S, Das DS, Tai YT, Carrasco RD, Chauhan D, and Anderson KC (2016). Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma. Leukemia 30, 1877–1886. 10.1038/leu.2016.97. - DOI - PMC - PubMed
1. Zheng X, Guo Y, Chen Y, Chen M, Lin Z, Wu Y, and Chen Y (2015). Knockdown of Adhesion-Regulating Molecule 1 Inhibits Proliferation in HL60 Cells. Acta Haematol 134, 88–100. 10.1159/000369916. - DOI - PubMed
1. Osei-Amponsa V, Sridharan V, Tandon M, Evans CN, Klarmann K, Cheng KT, Lack J, Chari R, and Walters KJ (2020). Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. Mol Cell Biol 40. 10.1128/MCB.00122-20. - DOI - PMC - PubMed
1. Jang SH, Park JW, Kim HR, Seong JK, and Kim HK (2014). ADRM1 gene amplification is a candidate driver for metastatic gastric cancers. Clin Exp Metastasis 31, 727–733. 10.1007/s10585-014-9663-4. - DOI - PubMed

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[1] Osei-Amponsa V, and Walters KJ (2022). Proteasome substrate receptors and their therapeutic potential. Trends Biochem Sci 47, 950–964. 10.1016/j.tibs.2022.06.006. - DOI - PMC - PubMed

[2] Osei-Amponsa V, and Walters KJ (2022). Proteasome substrate receptors and their therapeutic potential. Trends Biochem Sci 47, 950–964. 10.1016/j.tibs.2022.06.006. - DOI - PMC - PubMed

[3] Song Y, Ray A, Li S, Das DS, Tai YT, Carrasco RD, Chauhan D, and Anderson KC (2016). Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma. Leukemia 30, 1877–1886. 10.1038/leu.2016.97. - DOI - PMC - PubMed

[4] Song Y, Ray A, Li S, Das DS, Tai YT, Carrasco RD, Chauhan D, and Anderson KC (2016). Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma. Leukemia 30, 1877–1886. 10.1038/leu.2016.97. - DOI - PMC - PubMed

[5] Zheng X, Guo Y, Chen Y, Chen M, Lin Z, Wu Y, and Chen Y (2015). Knockdown of Adhesion-Regulating Molecule 1 Inhibits Proliferation in HL60 Cells. Acta Haematol 134, 88–100. 10.1159/000369916. - DOI - PubMed

[6] Zheng X, Guo Y, Chen Y, Chen M, Lin Z, Wu Y, and Chen Y (2015). Knockdown of Adhesion-Regulating Molecule 1 Inhibits Proliferation in HL60 Cells. Acta Haematol 134, 88–100. 10.1159/000369916. - DOI - PubMed

[7] Osei-Amponsa V, Sridharan V, Tandon M, Evans CN, Klarmann K, Cheng KT, Lack J, Chari R, and Walters KJ (2020). Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. Mol Cell Biol 40. 10.1128/MCB.00122-20. - DOI - PMC - PubMed

[8] Osei-Amponsa V, Sridharan V, Tandon M, Evans CN, Klarmann K, Cheng KT, Lack J, Chari R, and Walters KJ (2020). Impact of Losing hRpn13 Pru or UCHL5 on Proteasome Clearance of Ubiquitinated Proteins and RA190 Cytotoxicity. Mol Cell Biol 40. 10.1128/MCB.00122-20. - DOI - PMC - PubMed

[9] Jang SH, Park JW, Kim HR, Seong JK, and Kim HK (2014). ADRM1 gene amplification is a candidate driver for metastatic gastric cancers. Clin Exp Metastasis 31, 727–733. 10.1007/s10585-014-9663-4. - DOI - PubMed

[10] Jang SH, Park JW, Kim HR, Seong JK, and Kim HK (2014). ADRM1 gene amplification is a candidate driver for metastatic gastric cancers. Clin Exp Metastasis 31, 727–733. 10.1007/s10585-014-9663-4. - DOI - PubMed

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hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50

Affiliations

hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50

Authors

Affiliations

Abstract

Conflict of interest statement

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