The p97/VCP segregase is essential for arsenic induced degradation of PML and PML-RARA

Ellis G. Jaffray; Michael H. Tatham; Barbara Mojsa; Magda Liczmanska; Alejandro Rojas-Fernandez; Yili Yin; Graeme Ball; Ronald T. Hay

doi:10.1083/jcb.202201027

The p97/VCP segregase is essential for arsenic induced degradation of PML and PML-RARA

Ellis G. Jaffray, Michael H. Tatham, Barbara Mojsa, Magda Liczmanska, Alejandro Rojas-Fernandez, Yili Yin, Graeme Ball, Ronald T. Hay (Lead / Corresponding author)

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Abstract

Acute Promyelocytic Leukemia is caused by expression of the oncogenic Promyelocytic Leukemia (PML)–Retinoic Acid Receptor Alpha (RARA) fusion protein. Therapy with arsenic trioxide results in degradation of PML-RARA and PML and cures the disease. Modification of PML and PML-RARA with SUMO and ubiquitin precedes ubiquitin-mediated proteolysis. To identify additional components of this pathway, we performed proteomics on PML bodies. This revealed that association of p97/VCP segregase with PML bodies is increased after arsenic treatment. Pharmacological inhibition of p97 altered the number, morphology, and size of PML bodies, accumulated SUMO and ubiquitin modified PML and blocked arsenic-induced degradation of PML-RARA and PML. p97 localized to PML bodies in response to arsenic, and siRNA-mediated depletion showed that p97 cofactors UFD1 and NPLOC4 were critical for PML degradation. Thus, the UFD1-NPLOC4-p97 segregase complex is required to extract poly-ubiquitinated, poly-SUMOylated PML from PML bodies, prior to degradation by the proteasome.

Original language	English
Article number	e202201027
Number of pages	19
Journal	Journal of Cell Biology
Volume	222
Issue number	4
DOIs	https://doi.org/10.1083/jcb.202201027
Publication status	Published - 28 Feb 2023

Keywords

Cancer
Protein homeostasis

ASJC Scopus subject areas

Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1083/jcb.202201027Licence: CC BY

Final Published VersionFinal published version, 6.83 MBLicence: CC BY

Cite this

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title = "The p97/VCP segregase is essential for arsenic induced degradation of PML and PML-RARA",

abstract = "Acute Promyelocytic Leukemia is caused by expression of the oncogenic Promyelocytic Leukemia (PML)–Retinoic Acid Receptor Alpha (RARA) fusion protein. Therapy with arsenic trioxide results in degradation of PML-RARA and PML and cures the disease. Modification of PML and PML-RARA with SUMO and ubiquitin precedes ubiquitin-mediated proteolysis. To identify additional components of this pathway, we performed proteomics on PML bodies. This revealed that association of p97/VCP segregase with PML bodies is increased after arsenic treatment. Pharmacological inhibition of p97 altered the number, morphology, and size of PML bodies, accumulated SUMO and ubiquitin modified PML and blocked arsenic-induced degradation of PML-RARA and PML. p97 localized to PML bodies in response to arsenic, and siRNA-mediated depletion showed that p97 cofactors UFD1 and NPLOC4 were critical for PML degradation. Thus, the UFD1-NPLOC4-p97 segregase complex is required to extract poly-ubiquitinated, poly-SUMOylated PML from PML bodies, prior to degradation by the proteasome.",

keywords = "Cancer, Protein homeostasis",

author = "Jaffray, {Ellis G.} and Tatham, {Michael H.} and Barbara Mojsa and Magda Liczmanska and Alejandro Rojas-Fernandez and Yili Yin and Graeme Ball and Hay, {Ronald T.}",

note = "Funding Information: This work was supported by an Investigator Award from Wellcome Trust (217196/Z/19/Z) and a Program grant from Cancer Research UK (C434/A21747) to R.T. Hay. M. Liczmanska was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement 765445 (UbiCode). Copyright: {\textcopyright} 2023 Jaffray et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).",

year = "2023",

month = feb,

day = "28",

doi = "10.1083/jcb.202201027",

language = "English",

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journal = "Journal of Cell Biology",

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T1 - The p97/VCP segregase is essential for arsenic induced degradation of PML and PML-RARA

AU - Jaffray, Ellis G.

AU - Tatham, Michael H.

AU - Mojsa, Barbara

AU - Liczmanska, Magda

AU - Rojas-Fernandez, Alejandro

AU - Yin, Yili

AU - Ball, Graeme

AU - Hay, Ronald T.

N1 - Funding Information: This work was supported by an Investigator Award from Wellcome Trust (217196/Z/19/Z) and a Program grant from Cancer Research UK (C434/A21747) to R.T. Hay. M. Liczmanska was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie grant agreement 765445 (UbiCode). Copyright: © 2023 Jaffray et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

PY - 2023/2/28

Y1 - 2023/2/28

N2 - Acute Promyelocytic Leukemia is caused by expression of the oncogenic Promyelocytic Leukemia (PML)–Retinoic Acid Receptor Alpha (RARA) fusion protein. Therapy with arsenic trioxide results in degradation of PML-RARA and PML and cures the disease. Modification of PML and PML-RARA with SUMO and ubiquitin precedes ubiquitin-mediated proteolysis. To identify additional components of this pathway, we performed proteomics on PML bodies. This revealed that association of p97/VCP segregase with PML bodies is increased after arsenic treatment. Pharmacological inhibition of p97 altered the number, morphology, and size of PML bodies, accumulated SUMO and ubiquitin modified PML and blocked arsenic-induced degradation of PML-RARA and PML. p97 localized to PML bodies in response to arsenic, and siRNA-mediated depletion showed that p97 cofactors UFD1 and NPLOC4 were critical for PML degradation. Thus, the UFD1-NPLOC4-p97 segregase complex is required to extract poly-ubiquitinated, poly-SUMOylated PML from PML bodies, prior to degradation by the proteasome.

AB - Acute Promyelocytic Leukemia is caused by expression of the oncogenic Promyelocytic Leukemia (PML)–Retinoic Acid Receptor Alpha (RARA) fusion protein. Therapy with arsenic trioxide results in degradation of PML-RARA and PML and cures the disease. Modification of PML and PML-RARA with SUMO and ubiquitin precedes ubiquitin-mediated proteolysis. To identify additional components of this pathway, we performed proteomics on PML bodies. This revealed that association of p97/VCP segregase with PML bodies is increased after arsenic treatment. Pharmacological inhibition of p97 altered the number, morphology, and size of PML bodies, accumulated SUMO and ubiquitin modified PML and blocked arsenic-induced degradation of PML-RARA and PML. p97 localized to PML bodies in response to arsenic, and siRNA-mediated depletion showed that p97 cofactors UFD1 and NPLOC4 were critical for PML degradation. Thus, the UFD1-NPLOC4-p97 segregase complex is required to extract poly-ubiquitinated, poly-SUMOylated PML from PML bodies, prior to degradation by the proteasome.

KW - Cancer

KW - Protein homeostasis

UR - https://www.biorxiv.org/content/10.1101/2023.01.15.524136v1

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DO - 10.1083/jcb.202201027

M3 - Article

C2 - 36880596

SN - 0021-9525

VL - 222

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 4

M1 - e202201027

ER -

The p97/VCP segregase is essential for arsenic induced degradation of PML and PML-RARA

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Establishing the Basis for Selectivity in the SUMO Spray (Investigator Award)

Harnessing the PML-SUMO-RNF4 Axis for Cancer Therapy (Programme Grant)

Cite this

The p97/VCP segregase is essential for arsenic induced degradation of PML and PML-RARA

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Establishing the Basis for Selectivity in the SUMO Spray (Investigator Award)

Harnessing the PML-SUMO-RNF4 Axis for Cancer Therapy (Programme Grant)

Cite this