Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling

Roni Levin-Konigsberg; Fernando Montaño-Rendón; Tal Keren-Kaplan; Ren Li; Braeden Ego; Sivakami Mylvaganam; Jessica E. DiCiccio; William S. Trimble; Michael C. Bassik; Juan S. Bonifacino; Gregory D. Fairn; Sergio Grinstein

doi:10.1038/s41556-019-0394-2

Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling

Roni Levin-Konigsberg, Fernando Montaño-Rendón, Tal Keren-Kaplan, Ren Li, Braeden Ego, Sivakami Mylvaganam, Jessica E. DiCiccio, William S. Trimble, Michael C. Bassik, Juan S. Bonifacino, Gregory D. Fairn, Sergio Grinstein

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

68 Citations (Scopus)

Abstract

Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4)P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4)P depletion and enrichment. Tubules emerged from PtdIns(4)P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4)P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4)P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.

Original language	English
Pages (from-to)	1234-1247
Number of pages	14
Journal	Nature Cell Biology
Volume	21
Issue number	10
DOIs	https://doi.org/10.1038/s41556-019-0394-2
Publication status	Published - Oct 1 2019
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the following grants and scholarships: Connaught International Scholarship for Doctoral Students from the University of Toronto and the National Council for Science and Technology/Consejo Nacional de Ciencia y Tecnología (CONACYT) of Mexico (to R.L.-K.) and FDN-143202 from the Canadian Institutes of Health Research (to S.G.). We thank J. Heddleston, S. Khuon and T. Leong-Chew from the AIC for training and support for LLSM. The AIC is a jointly-funded venture of the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute.

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus Subject Areas

Cell Biology

Access to Document

10.1038/s41556-019-0394-2

Cite this

Levin-Konigsberg, R., Montaño-Rendón, F., Keren-Kaplan, T., Li, R., Ego, B., Mylvaganam, S., DiCiccio, J. E., Trimble, W. S., Bassik, M. C., Bonifacino, J. S., Fairn, G. D., & Grinstein, S. (2019). Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling. Nature Cell Biology, 21(10), 1234-1247. https://doi.org/10.1038/s41556-019-0394-2

Levin-Konigsberg, R, Montaño-Rendón, F, Keren-Kaplan, T, Li, R, Ego, B, Mylvaganam, S, DiCiccio, JE, Trimble, WS, Bassik, MC, Bonifacino, JS, Fairn, GD & Grinstein, S 2019, 'Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling', Nature Cell Biology, vol. 21, no. 10, pp. 1234-1247. https://doi.org/10.1038/s41556-019-0394-2

@article{7ff38684387c4f10b5480a5b09fe4d78,

title = "Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling",

abstract = "Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4)P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4)P depletion and enrichment. Tubules emerged from PtdIns(4)P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4)P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4)P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.",

author = "Roni Levin-Konigsberg and Fernando Monta{\~n}o-Rend{\'o}n and Tal Keren-Kaplan and Ren Li and Braeden Ego and Sivakami Mylvaganam and DiCiccio, {Jessica E.} and Trimble, {William S.} and Bassik, {Michael C.} and Bonifacino, {Juan S.} and Fairn, {Gregory D.} and Sergio Grinstein",

note = "Funding Information: This work was supported by the following grants and scholarships: Connaught International Scholarship for Doctoral Students from the University of Toronto and the National Council for Science and Technology/Consejo Nacional de Ciencia y Tecnolog{\'i}a (CONACYT) of Mexico (to R.L.-K.) and FDN-143202 from the Canadian Institutes of Health Research (to S.G.). We thank J. Heddleston, S. Khuon and T. Leong-Chew from the AIC for training and support for LLSM. The AIC is a jointly-funded venture of the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = oct,

day = "1",

doi = "10.1038/s41556-019-0394-2",

language = "English",

volume = "21",

pages = "1234--1247",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "10",

}

TY - JOUR

T1 - Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling

AU - Levin-Konigsberg, Roni

AU - Montaño-Rendón, Fernando

AU - Keren-Kaplan, Tal

AU - Li, Ren

AU - Ego, Braeden

AU - Mylvaganam, Sivakami

AU - DiCiccio, Jessica E.

AU - Trimble, William S.

AU - Bassik, Michael C.

AU - Bonifacino, Juan S.

AU - Fairn, Gregory D.

AU - Grinstein, Sergio

N1 - Funding Information: This work was supported by the following grants and scholarships: Connaught International Scholarship for Doctoral Students from the University of Toronto and the National Council for Science and Technology/Consejo Nacional de Ciencia y Tecnología (CONACYT) of Mexico (to R.L.-K.) and FDN-143202 from the Canadian Institutes of Health Research (to S.G.). We thank J. Heddleston, S. Khuon and T. Leong-Chew from the AIC for training and support for LLSM. The AIC is a jointly-funded venture of the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4)P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4)P depletion and enrichment. Tubules emerged from PtdIns(4)P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4)P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4)P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.

AB - Phosphoinositides have a pivotal role in the maturation of nascent phagosomes into microbicidal phagolysosomes. Following degradation of their contents, mature phagolysosomes undergo resolution, a process that remains largely uninvestigated. Here we studied the role of phosphoinositides in phagolysosome resolution. Phosphatidylinositol-4-phosphate (PtdIns(4)P), which is abundant in maturing phagolysosomes, was depleted as they tubulated and resorbed. Depletion was caused, in part, by transfer of phagolysosomal PtdIns(4)P to the endoplasmic reticulum, a process mediated by oxysterol-binding protein-related protein 1L (ORP1L), a RAB7 effector. ORP1L formed discrete tethers between the phagolysosome and the endoplasmic reticulum, resulting in distinct regions with alternating PtdIns(4)P depletion and enrichment. Tubules emerged from PtdIns(4)P-rich regions, where ADP-ribosylation factor-like protein 8B (ARL8B) and SifA- and kinesin-interacting protein/pleckstrin homology domain-containing family M member 2 (SKIP/PLEKHM2) accumulated. SKIP binds preferentially to monophosphorylated phosphoinositides, of which PtdIns(4)P is most abundant in phagolysosomes, contributing to their tubulation. Accordingly, premature hydrolysis of PtdIns(4)P impaired SKIP recruitment and phagosome resolution. Thus, resolution involves phosphoinositides and tethering of phagolysosomes to the endoplasmic reticulum.

UR - http://www.scopus.com/inward/record.url?scp=85074154511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074154511&partnerID=8YFLogxK

U2 - 10.1038/s41556-019-0394-2

DO - 10.1038/s41556-019-0394-2

M3 - Article

C2 - 31570833

AN - SCOPUS:85074154511

SN - 1465-7392

VL - 21

SP - 1234

EP - 1247

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 10

ER -

Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Access to Document

Other files and links

Fingerprint

Cite this