Sorting nexin 5 mediates virus-induced autophagy and immunity

Boris Simonetti; Pete J Cullen; Ramnik Xavier; et al.

doi:10.1038/s41586-020-03056-z

Sorting nexin 5 mediates virus-induced autophagy and immunity

Boris Simonetti, Pete J Cullen , Ramnik Xavier^*, et al.

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

60 Citations (Scopus)

413 Downloads (Pure)

Abstract

Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism—SNX5-dependent PI3KC3-C1 activation at endosomes—for initiation of autophagy during viral infection.

Original language	English
Pages (from-to)	456–461
Number of pages	37
Journal	Nature
Volume	589
DOIs	https://doi.org/10.1038/s41586-020-03056-z
Publication status	Published - 16 Dec 2020

UN SDGs

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

Access to Document

10.1038/s41586-020-03056-z

Full-text PDF (author accepted manuscript)
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 7.21 MB
Supplementary information GuidePDF
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 25.9 KB
Supplementary Table 1 PDF
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 11.8 MB
Supplementary Table 2 PDF
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 25 MB
Supplementary Table 3 PDF
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 1.87 MB
Supplementary Table 4 PDF
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 385 KB
Supplementary Table 5 PDF
This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Springer Nature at https://doi.org/10.1038/s41586-020-03056-z. Please refer to any applicable terms of use of the publisher.
Accepted author manuscript, 92.2 KB

Handle.net

Persistent link

Cite this

@article{16aea7620b604cbda973574d118bdccd,

title = "Sorting nexin 5 mediates virus-induced autophagy and immunity",

abstract = "Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism—SNX5-dependent PI3KC3-C1 activation at endosomes—for initiation of autophagy during viral infection.",

author = "Boris Simonetti and Cullen, {Pete J} and Ramnik Xavier and {et al.}",

year = "2020",

month = dec,

day = "16",

doi = "10.1038/s41586-020-03056-z",

language = "English",

volume = "589",

pages = "456–461",

journal = "Nature",

issn = "0028-0836",

publisher = "Springer Nature",

}

TY - JOUR

T1 - Sorting nexin 5 mediates virus-induced autophagy and immunity

AU - Simonetti, Boris

AU - Cullen , Pete J

AU - Xavier, Ramnik

AU - et al.

PY - 2020/12/16

Y1 - 2020/12/16

N2 - Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism—SNX5-dependent PI3KC3-C1 activation at endosomes—for initiation of autophagy during viral infection.

AB - Autophagy, a process of degradation that occurs via the lysosomal pathway, has an essential role in multiple aspects of immunity, including immune system development, regulation of innate and adaptive immune and inflammatory responses, selective degradation of intracellular microorganisms, and host protection against infectious diseases1,2. Autophagy is known to be induced by stimuli such as nutrient deprivation and suppression of mTOR, but little is known about how autophagosomal biogenesis is initiated in mammalian cells in response to viral infection. Here, using genome-wide short interfering RNA screens, we find that the endosomal protein sorting nexin 5 (SNX5)3,4 is essential for virus-induced, but not for basal, stress- or endosome-induced, autophagy. We show that SNX5 deletion increases cellular susceptibility to viral infection in vitro, and that Snx5 knockout in mice enhances lethality after infection with several human viruses. Mechanistically, SNX5 interacts with beclin 1 and ATG14-containing class III phosphatidylinositol-3-kinase (PI3KC3) complex 1 (PI3KC3-C1), increases the lipid kinase activity of purified PI3KC3-C1, and is required for endosomal generation of phosphatidylinositol-3-phosphate (PtdIns(3)P) and recruitment of the PtdIns(3)P-binding protein WIPI2 to virion-containing endosomes. These findings identify a context- and organelle-specific mechanism—SNX5-dependent PI3KC3-C1 activation at endosomes—for initiation of autophagy during viral infection.

U2 - 10.1038/s41586-020-03056-z

DO - 10.1038/s41586-020-03056-z

M3 - Article (Academic Journal)

C2 - 33328639

SN - 0028-0836

VL - 589

SP - 456

EP - 461

JO - Nature

JF - Nature

ER -

Sorting nexin 5 mediates virus-induced autophagy and immunity

Abstract

UN SDGs

Access to Document

Handle.net

Fingerprint

Cite this