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 Barisic; Jens S Andersen; Simon Bekker-Jensen; Anders H Lund; Vladimir V Rogov; Elena Papaleo; Letizia Lanzetti; Daniela De Zio; Francesco Cecconi

doi:10.1038/s41467-019-12094-9

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

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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 language	English
Article number	4176
Journal	Nature Communications
Volume	10
Issue number	1
Pages (from-to)	1-19
Number of pages	19
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-019-12094-9
Publication status	Published - 1 Dec 2019

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Holdgaard, S. G., Cianfanelli, V., Pupo, E., Lambrughi, M., Lubas, M., Nielsen, J. C., Eibes, S., Maiani, E., Harder, L. M., Wesch, N., Foged, M. M., Maeda, K., Nazio, F., de la Ballina, L. R., Dötsch, V., Brech, A., Frankel, L. B., Jäättelä, M., Locatelli, F., ... Cecconi, F. (2019). Selective autophagy maintains centrosome integrity and accurate mitosis by turnover of centriolar satellites. Nature Communications, 10(1), 1-19. [4176]. https://doi.org/10.1038/s41467-019-12094-9

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, no. 1, 4176, pp. 1-19. https://doi.org/10.1038/s41467-019-12094-9

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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.",

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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 - 2019/12/1

Y1 - 2019/12/1

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

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EP - 19

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4176

ER -

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

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