Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites

Søs Grønbæk Holdgaard, Valentina Cianfanelli, Emanuela Pupo, Matteo Lambrughi, Michal Lubas, Julie C. Nielsen, Susana Eibes, Emiliano Maiani, Lea M. Harder, Nicole Wesch, Mads Møller Foged, Kenji Maeda, Francesca Nazio, Laura R. de la Ballina, Volker Dötsch, Andreas Brech, Lisa B. Frankel, Marja Jäättelä, Franco Locatelli, Marin BarisicJens S. Andersen, Simon Bekker-Jensen, Anders H. Lund, Vladimir V. Rogov, Elena Papaleo, Letizia Lanzetti, Daniela De Zio, Francesco Cecconi*

*Corresponding author for this work

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Abstract

The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.

Original languageEnglish
Article number4176
JournalNature Communications
Volume10
Pages (from-to)4176
Number of pages19
ISSN2041-1723
DOIs
Publication statusPublished - 2019

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Homeostasis
Neoplasms

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Holdgaard, S. G., Cianfanelli, V., Pupo, E., Lambrughi, M., Lubas, M., Nielsen, J. C., ... Cecconi, F. (2019). Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites. Nature Communications, 10, 4176. [4176]. https://doi.org/10.1038/s41467-019-12094-9
Holdgaard, Søs Grønbæk ; Cianfanelli, Valentina ; Pupo, Emanuela ; Lambrughi, Matteo ; Lubas, Michal ; Nielsen, Julie C. ; Eibes, Susana ; Maiani, Emiliano ; Harder, Lea M. ; Wesch, Nicole ; Foged, Mads Møller ; Maeda, Kenji ; Nazio, Francesca ; de la Ballina, Laura R. ; Dötsch, Volker ; Brech, Andreas ; Frankel, Lisa B. ; Jäättelä, Marja ; Locatelli, Franco ; Barisic, Marin ; Andersen, Jens S. ; Bekker-Jensen, Simon ; Lund, Anders H. ; Rogov, Vladimir V. ; Papaleo, Elena ; Lanzetti, Letizia ; De Zio, Daniela ; Cecconi, Francesco. / Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites. In: Nature Communications. 2019 ; Vol. 10. pp. 4176.
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title = "Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites",
abstract = "The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.",
author = "Holdgaard, {S{\o}s Gr{\o}nb{\ae}k} and Valentina Cianfanelli and Emanuela Pupo and Matteo Lambrughi and Michal Lubas and Nielsen, {Julie C.} and Susana Eibes and Emiliano Maiani and Harder, {Lea M.} and Nicole Wesch and Foged, {Mads M{\o}ller} and Kenji Maeda and Francesca Nazio and {de la Ballina}, {Laura R.} and Volker D{\"o}tsch and Andreas Brech and Frankel, {Lisa B.} and Marja J{\"a}{\"a}ttel{\"a} and Franco Locatelli and Marin Barisic and Andersen, {Jens S.} and Simon Bekker-Jensen and Lund, {Anders H.} and Rogov, {Vladimir V.} and Elena Papaleo and Letizia Lanzetti and {De Zio}, Daniela and Francesco Cecconi",
year = "2019",
doi = "10.1038/s41467-019-12094-9",
language = "English",
volume = "10",
pages = "4176",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

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Holdgaard, SG, Cianfanelli, V, Pupo, E, Lambrughi, M, Lubas, M, Nielsen, JC, Eibes, S, Maiani, E, Harder, LM, Wesch, N, Foged, MM, Maeda, K, Nazio, F, de la Ballina, LR, Dötsch, V, Brech, A, Frankel, LB, Jäättelä, M, Locatelli, F, Barisic, M, Andersen, JS, Bekker-Jensen, S, Lund, AH, Rogov, VV, Papaleo, E, Lanzetti, L, De Zio, D & Cecconi, F 2019, 'Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites', Nature Communications, vol. 10, 4176, pp. 4176. https://doi.org/10.1038/s41467-019-12094-9

Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites. / Holdgaard, Søs Grønbæk; Cianfanelli, Valentina; Pupo, Emanuela; Lambrughi, Matteo; Lubas, Michal; Nielsen, Julie C.; Eibes, Susana; Maiani, Emiliano; Harder, Lea M.; Wesch, Nicole; Foged, Mads Møller; Maeda, Kenji; Nazio, Francesca; de la Ballina, Laura R.; Dötsch, Volker; Brech, Andreas; Frankel, Lisa B.; Jäättelä, Marja; Locatelli, Franco; Barisic, Marin; Andersen, Jens S.; Bekker-Jensen, Simon; Lund, Anders H.; Rogov, Vladimir V.; Papaleo, Elena; Lanzetti, Letizia; De Zio, Daniela; Cecconi, Francesco.

In: Nature Communications, Vol. 10, 4176, 2019, p. 4176.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites

AU - Holdgaard, Søs Grønbæk

AU - Cianfanelli, Valentina

AU - Pupo, Emanuela

AU - Lambrughi, Matteo

AU - Lubas, Michal

AU - Nielsen, Julie C.

AU - Eibes, Susana

AU - Maiani, Emiliano

AU - Harder, Lea M.

AU - Wesch, Nicole

AU - Foged, Mads Møller

AU - Maeda, Kenji

AU - Nazio, Francesca

AU - de la Ballina, Laura R.

AU - Dötsch, Volker

AU - Brech, Andreas

AU - Frankel, Lisa B.

AU - Jäättelä, Marja

AU - Locatelli, Franco

AU - Barisic, Marin

AU - Andersen, Jens S.

AU - Bekker-Jensen, Simon

AU - Lund, Anders H.

AU - Rogov, Vladimir V.

AU - Papaleo, Elena

AU - Lanzetti, Letizia

AU - De Zio, Daniela

AU - Cecconi, Francesco

PY - 2019

Y1 - 2019

N2 - The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.

AB - The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.

U2 - 10.1038/s41467-019-12094-9

DO - 10.1038/s41467-019-12094-9

M3 - Journal article

C2 - 31519908

AN - SCOPUS:85072165167

VL - 10

SP - 4176

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4176

ER -