Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL

Maria Giovanna De Leo; Leopoldo Staiano; Mariella Vicinanza; Alessandro Luciani; Annamaria Carissimo; Margherita Mutarelli; Antonella Di Campli; Elena Polishchuk; Giuseppe Di Tullio; Valentina Morra; Elena Levtchenko; Francesca Oltrabella; Tobias Starborg; Michele Santoro; Diego di Bernardo; Olivier Devuyst; Martin Lowe; Diego L Medina; Andrea Ballabio; Maria Antonietta De Matteis

doi:10.1038/ncb3386

Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL

Maria Giovanna De Leo, Leopoldo Staiano, Mariella Vicinanza, Alessandro Luciani, Annamaria Carissimo, Margherita Mutarelli, Antonella Di Campli, Elena Polishchuk, Giuseppe Di Tullio, Valentina Morra, Elena Levtchenko, Francesca Oltrabella, Tobias Starborg, Michele Santoro, Diego di Bernardo, Olivier Devuyst, Martin Lowe, Diego L Medina, Andrea Ballabio, Maria Antonietta De Matteis

Research output: Contribution to journal › Article › peer-review

132 Downloads (Pure)

Abstract

Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome-lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients.

Original language	English
Pages (from-to)	839-50
Number of pages	12
Journal	Nature Cell Biology
Volume	18
Issue number	8
Early online date	11 Jul 2016
DOIs	https://doi.org/10.1038/ncb3386
Publication status	Published - Aug 2016

Access to Document

10.1038/ncb3386

40837980.50979_4_merged_1463668604Accepted author manuscript, 108 MB

Cite this

De Leo, M. G., Staiano, L., Vicinanza, M., Luciani, A., Carissimo, A., Mutarelli, M., Di Campli, A., Polishchuk, E., Di Tullio, G., Morra, V., Levtchenko, E., Oltrabella, F., Starborg, T., Santoro, M., di Bernardo, D., Devuyst, O., Lowe, M., Medina, D. L., Ballabio, A., & De Matteis, M. A. (2016). Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nature Cell Biology, 18(8), 839-50. https://doi.org/10.1038/ncb3386

@article{e3c9680436e24fd0895a483b84cbf1c5,

title = "Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL",

abstract = "Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome-lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients.",

author = "{De Leo}, {Maria Giovanna} and Leopoldo Staiano and Mariella Vicinanza and Alessandro Luciani and Annamaria Carissimo and Margherita Mutarelli and {Di Campli}, Antonella and Elena Polishchuk and {Di Tullio}, Giuseppe and Valentina Morra and Elena Levtchenko and Francesca Oltrabella and Tobias Starborg and Michele Santoro and {di Bernardo}, Diego and Olivier Devuyst and Martin Lowe and Medina, {Diego L} and Andrea Ballabio and {De Matteis}, {Maria Antonietta}",

year = "2016",

month = aug,

doi = "10.1038/ncb3386",

language = "English",

volume = "18",

pages = "839--50",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Research",

number = "8",

}

De Leo, MG, Staiano, L, Vicinanza, M, Luciani, A, Carissimo, A, Mutarelli, M, Di Campli, A, Polishchuk, E, Di Tullio, G, Morra, V, Levtchenko, E, Oltrabella, F, Starborg, T, Santoro, M, di Bernardo, D, Devuyst, O, Lowe, M, Medina, DL, Ballabio, A & De Matteis, MA 2016, 'Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL', Nature Cell Biology, vol. 18, no. 8, pp. 839-50. https://doi.org/10.1038/ncb3386

TY - JOUR

T1 - Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL

AU - De Leo, Maria Giovanna

AU - Staiano, Leopoldo

AU - Vicinanza, Mariella

AU - Luciani, Alessandro

AU - Carissimo, Annamaria

AU - Mutarelli, Margherita

AU - Di Campli, Antonella

AU - Polishchuk, Elena

AU - Di Tullio, Giuseppe

AU - Morra, Valentina

AU - Levtchenko, Elena

AU - Oltrabella, Francesca

AU - Starborg, Tobias

AU - Santoro, Michele

AU - di Bernardo, Diego

AU - Devuyst, Olivier

AU - Lowe, Martin

AU - Medina, Diego L

AU - Ballabio, Andrea

AU - De Matteis, Maria Antonietta

PY - 2016/8

Y1 - 2016/8

N2 - Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome-lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients.

AB - Phosphoinositides (PtdIns) control fundamental cell processes, and inherited defects of PtdIns kinases or phosphatases cause severe human diseases, including Lowe syndrome due to mutations in OCRL, which encodes a PtdIns(4,5)P2 5-phosphatase. Here we unveil a lysosomal response to the arrival of autophagosomal cargo in which OCRL plays a key part. We identify mitochondrial DNA and TLR9 as the cargo and the receptor that triggers and mediates, respectively, this response. This lysosome-cargo response is required to sustain the autophagic flux and involves a local increase in PtdIns(4,5)P2 that is confined in space and time by OCRL. Depleting or inhibiting OCRL leads to an accumulation of lysosomal PtdIns(4,5)P2, an inhibitor of the calcium channel mucolipin-1 that controls autophagosome-lysosome fusion. Hence, autophagosomes accumulate in OCRL-depleted cells and in the kidneys of Lowe syndrome patients. Importantly, boosting the activity of mucolipin-1 with selective agonists restores the autophagic flux in cells from Lowe syndrome patients.

U2 - 10.1038/ncb3386

DO - 10.1038/ncb3386

M3 - Article

C2 - 27398910

SN - 1465-7392

VL - 18

SP - 839

EP - 850

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -

Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL

Abstract

Access to Document

Fingerprint

Cite this