RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly.
The study of macroautophagy in mammalian cells has described induction, vesicle nucleation, and membrane elongation complexes as key signaling intermediates driving autophagosome biogenesis. How these components are recruited to nascent autophagosomes is poorly understood, and although much is known about signaling mechanisms that restrain autophagy, the nature of positive inductive signals that can promote autophagy remain cryptic. We find that the Ras-like small G protein, RalB, is localized to nascent autophagosomes and is activated on nutrient deprivation. RalB and its effector Exo84 are required for nutrient starvation-induced autophagocytosis, and RalB activation is sufficient to promote autophagosome formation. Through direct binding to Exo84, RalB induces the assembly of catalytically active ULK1 and Beclin1-VPS34 complexes on the exocyst, which are required for isolation membrane formation and maturation. Thus, RalB signaling is a primary adaptive response to nutrient limitation that directly engages autophagocytosis through mobilization of the core vesicle nucleation machinery.
Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390-9039, USA.
Brian O
BO
Bodemann
Anthony
A
Orvedahl
Tzuling
T
Cheng
Rosalyn R
RR
Ram
Yi-Hung
YH
Ou
Etienne
E
Formstecher
Mekhala
M
Maiti
C Clayton
CC
Hazelett
Eric M
EM
Wauson
Maria
M
Balakireva
Jacques H
JH
Camonis
Charles
C
Yeaman
Beth
B
Levine
Michael A
MA
White
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002460:Cell Line; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000502:physiology; D015398:Signal Transduction; D013312:Stress, Physiological; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C480857:EXOC8 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C483163:Ralb protein, human; D033921:Vesicular Transport Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D020725:ral GTP-Binding Proteins
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