The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy
Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, fo...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/10/2490 |
| _version_ | 1797533335502716928 |
|---|---|
| author | Abderrahman Chargui Amine Belaid Papa Diogop Ndiaye Véronique Imbert Michel Samson Jean-Marie Guigonis Michel Tauc Jean-François Peyron Philippe Poujeol Patrick Brest Paul Hofman Baharia Mograbi |
| author_facet | Abderrahman Chargui Amine Belaid Papa Diogop Ndiaye Véronique Imbert Michel Samson Jean-Marie Guigonis Michel Tauc Jean-François Peyron Philippe Poujeol Patrick Brest Paul Hofman Baharia Mograbi |
| author_sort | Abderrahman Chargui |
| collection | DOAJ |
| description | Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy—SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis. |
| first_indexed | 2024-03-10T11:14:02Z |
| format | Article |
| id | doaj.art-41013859a18e4463b3d04b0b658ab504 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:14:02Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-41013859a18e4463b3d04b0b658ab5042023-11-21T20:34:11ZengMDPI AGCancers2072-66942021-05-011310249010.3390/cancers13102490The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective AutophagyAbderrahman Chargui0Amine Belaid1Papa Diogop Ndiaye2Véronique Imbert3Michel Samson4Jean-Marie Guigonis5Michel Tauc6Jean-François Peyron7Philippe Poujeol8Patrick Brest9Paul Hofman10Baharia Mograbi11Université Côte d’Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, FranceUniversité Côte d’Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, FranceUniversité Côte d’Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, FranceUniversité Côte d’Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut National de la Santé et de la Recherche Médicale (INSERM), F-06204 Nice, FranceUniversité Côte d’Azur, Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Fréderic Joliot, Commissariat à l’Energie Atomique et aux énergies alternatives (CEA), F-06107 Nice, FranceUniversité Côte d’Azur, Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des sciences du vivant Fréderic Joliot, Commissariat à l’Energie Atomique et aux énergies alternatives (CEA), F-06107 Nice, FranceUniversité Côte d’Azur, Laboratoire de Physiomédecine Moléculaire, LP2M, Labex ICST, Centre National de la Recherche Scientifique (CNRS), F-06107 Nice, FranceUniversité Côte d’Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Institut National de la Santé et de la Recherche Médicale (INSERM), F-06204 Nice, FranceUniversité Côte d’Azur, Laboratoire de Physiomédecine Moléculaire, LP2M, Labex ICST, Centre National de la Recherche Scientifique (CNRS), F-06107 Nice, FranceUniversité Côte d’Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, FranceUniversité Côte d’Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, FranceUniversité Côte d’Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, FranceSignaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy—SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis.https://www.mdpi.com/2072-6694/13/10/2490K63-linked ubiquitinationtumor suppressionselective autophagystarvation-induced autophagyaggrephagyCYLD deubiquitinase |
| spellingShingle | Abderrahman Chargui Amine Belaid Papa Diogop Ndiaye Véronique Imbert Michel Samson Jean-Marie Guigonis Michel Tauc Jean-François Peyron Philippe Poujeol Patrick Brest Paul Hofman Baharia Mograbi The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy Cancers K63-linked ubiquitination tumor suppression selective autophagy starvation-induced autophagy aggrephagy CYLD deubiquitinase |
| title | The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy |
| title_full | The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy |
| title_fullStr | The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy |
| title_full_unstemmed | The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy |
| title_short | The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy |
| title_sort | carcinogen cadmium activates lysine 63 k63 linked ubiquitin dependent signaling and inhibits selective autophagy |
| topic | K63-linked ubiquitination tumor suppression selective autophagy starvation-induced autophagy aggrephagy CYLD deubiquitinase |
| url | https://www.mdpi.com/2072-6694/13/10/2490 |
| work_keys_str_mv | AT abderrahmanchargui thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT aminebelaid thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT papadiogopndiaye thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT veroniqueimbert thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT michelsamson thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT jeanmarieguigonis thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT micheltauc thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT jeanfrancoispeyron thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT philippepoujeol thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT patrickbrest thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT paulhofman thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT bahariamograbi thecarcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT abderrahmanchargui carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT aminebelaid carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT papadiogopndiaye carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT veroniqueimbert carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT michelsamson carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT jeanmarieguigonis carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT micheltauc carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT jeanfrancoispeyron carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT philippepoujeol carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT patrickbrest carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT paulhofman carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy AT bahariamograbi carcinogencadmiumactivateslysine63k63linkedubiquitindependentsignalingandinhibitsselectiveautophagy |