PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis

Hao Liu; Wenxia Shao; Wei Liu; Weina Shang; Jun-Ping Liu; Liquan Wang; Chao Tong

doi:10.1080/15548627.2023.2222556

PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis

Autophagy. 2023 Oct;19(10):2682-2701. doi: 10.1080/15548627.2023.2222556. Epub 2023 Jun 13.

Authors

Hao Liu^{1

2}, Wenxia Shao^{1

2}, Wei Liu^{1

2}, Weina Shang¹, Jun-Ping Liu³, Liquan Wang², Chao Tong^{1

2

3

4}

Affiliations

¹ MOE Key Laboratory for Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
² Department of Gastroenterology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang, China.
⁴ Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.

PMID: 37289040
PMCID: PMC10472871 (available on 2024-06-13)
DOI: 10.1080/15548627.2023.2222556

Abstract

Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation - the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.Abbreviations: Atg1: Autophagy-related 1; Atg8: Autophagy-related 8; Atg9: Autophagy-related 9; Atg12: Autophagy-related 12; cert: ceramide transfer protein; Cp1/CathL: cysteine proteinase-1; CTL: control; ER: endoplasmic reticulum; ERMCS: ER-mitochondria contact site; fwd: four wheel drive; GM130: Golgi matrix protein 130 kD; Osbp: Oxysterol binding protein; PG: phagophore; PtdIns4K: phosphatidylinositol 4-kinase; Pi4KIIα: Phosphatidylinositol 4-kinase II α; Pi4KIIIα: Phosphatidylinositol 4-kinase III α; PtdIns4P: phosphatidylinositol-4-phosphate; PR: photoreceptor cell; RT: room temperature; Sac1: Sac1 phosphatase; Stv: starvation; Syx17: Syntaxin 17; TEM: transmission electron microscopy; VAP: VAMP-associated protein.

Keywords: Drosophila; Golgi apparatus; PtdIns4P; autophagy; endoplasmic reticulum-autolysosome contacts.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Phosphatidylinositol 4-Kinase* / metabolism
Autophagy*
Carrier Proteins / metabolism
Ceramides / metabolism
Endoplasmic Reticulum / metabolism
Homeostasis
Lysosomes / metabolism
Phosphoric Monoester Hydrolases / metabolism

Substances

phosphatidylinositol 4-phosphate
1-Phosphatidylinositol 4-Kinase
Carrier Proteins
Ceramides
Phosphoric Monoester Hydrolases

Grants and funding

Dr. Tong Chao is supported by National Natural Science Foundation of China (92254305, 92157201, 32030027, 91754103), Fundamental research funds for the central universities, and Shenzhen Bay Scholars Program. Dr. Liu Hao is supported by National Natural Science Foundation of China (32100599).