TY - JOUR
T1 - PtdIns(4,5)P2 signaling regulates ATG14 and autophagy
AU - Tan, Xiaojun
AU - Thapa, Narendra
AU - Liao, Yihan
AU - Choi, Suyong
AU - Anderson, Richard A.
N1 - Funding Information:
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1523145113/-/DCSupplemental. We thank all members of the R.A.A. group for discussions and reagents. This study was supported by NIH Grants CA104708 and GM057549 (to R.A.A.); Howard Hughes Medical Institute International Student Research Fellowship 59107631 (to X.T.); and a Hilldale Undergraduate/Faculty Research fellowship (to Y.L.).
PY - 2016/9/27
Y1 - 2016/9/27
N2 - Autophagy is a regulated self-digestion pathway with fundamental roles in cell homeostasis and diseases. Autophagy is regulated by coordinated actions of a series of autophagy-related (ATG) proteins. The Barkor/ATG14(L)-VPS34 (a class III phosphatidylinositol 3-kinase) complex and its product phosphatidylinositol 3-phosphate [PtdIns(3)P] play key roles in autophagy initiation. ATG14 contains a C-terminal Barkor/ATG14(L) autophagosome-targeting sequence (BATS) domain that senses the curvature of PtdIns(3)P-containing membrane. The BATS domain also strongly binds PtdIns(4,5)P2 , but the functional significance has been unclear. Here we show that ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme that generates PtdIns(4,5)P2 in mammalian cells. Autophagosomes have associated PIPKIγi5 and PtdIns(4,5)P2 that are colocalized with late endosomes and the endoplasmic reticulum. PtdIns(4,5)P2 generation at these sites requires PIPKIγi5. Loss of PIPKIγi5 results in a loss of ATG14, UV irradiation resistance-associated gene, and Beclin 1 and a block of autophagy. PtdIns(4,5)P2 binding to the ATG14-BATS domain regulates ATG14 interaction with VPS34 and Beclin 1, and thus plays a key role in ATG14 complex assembly and autophagy initiation. This study identifies an unexpected role for PtdIns(4,5)P2 signaling in the regulation of ATG14 complex and autophagy.
AB - Autophagy is a regulated self-digestion pathway with fundamental roles in cell homeostasis and diseases. Autophagy is regulated by coordinated actions of a series of autophagy-related (ATG) proteins. The Barkor/ATG14(L)-VPS34 (a class III phosphatidylinositol 3-kinase) complex and its product phosphatidylinositol 3-phosphate [PtdIns(3)P] play key roles in autophagy initiation. ATG14 contains a C-terminal Barkor/ATG14(L) autophagosome-targeting sequence (BATS) domain that senses the curvature of PtdIns(3)P-containing membrane. The BATS domain also strongly binds PtdIns(4,5)P2 , but the functional significance has been unclear. Here we show that ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme that generates PtdIns(4,5)P2 in mammalian cells. Autophagosomes have associated PIPKIγi5 and PtdIns(4,5)P2 that are colocalized with late endosomes and the endoplasmic reticulum. PtdIns(4,5)P2 generation at these sites requires PIPKIγi5. Loss of PIPKIγi5 results in a loss of ATG14, UV irradiation resistance-associated gene, and Beclin 1 and a block of autophagy. PtdIns(4,5)P2 binding to the ATG14-BATS domain regulates ATG14 interaction with VPS34 and Beclin 1, and thus plays a key role in ATG14 complex assembly and autophagy initiation. This study identifies an unexpected role for PtdIns(4,5)P2 signaling in the regulation of ATG14 complex and autophagy.
KW - ATG14
KW - Atg14-bats domain
KW - Autophagy
KW - PIPKIγi5
KW - PtdIns(4 5)p2
UR - http://www.scopus.com/inward/record.url?scp=84989880400&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84989880400&partnerID=8YFLogxK
U2 - 10.1073/pnas.1523145113
DO - 10.1073/pnas.1523145113
M3 - Article
C2 - 27621469
AN - SCOPUS:84989880400
SN - 0027-8424
VL - 113
SP - 10896
EP - 10901
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
ER -