The RAB GTPase RAB18 modulates macroautophagy and proteostasis.
Macroautophagy is a conserved degradative pathway and its deterioration is linked to disturbances in cellular proteostasis and multiple diseases. Here, we show that the RAB GTPase RAB18 modulates autophagy in primary human fibroblasts. The knockdown of RAB18 results in a decreased autophagic activity, while its overexpression enhances the degradative pathway. Importantly, this function of RAB18 is dependent on RAB3GAP1 and RAB3GAP2, which might act as RAB GEFs and stimulate the activity of the RAB GTPase. Moreover, the knockdown of RAB18 deteriorates proteostasis and results in the intracellular accumulation of ubiquitinated degradation-prone proteins. Thus, the RAB GTPase RAB18 is a positive modulator of autophagy and is relevant for the maintenance of cellular proteostasis.
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany. Electronic address: afeldman@uni-mainz.de.
Anne
A
Feldmann
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany. Electronic address: fbekbula@uni-mainz.de.
Fazilet
F
Bekbulat
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany. Electronic address: duerk@uni-mainz.de.
Heike
H
Huesmann
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry und Pathobiochemistry, Ruhr University Bochum, 44801 Bochum, Germany. Electronic address: sarah.ulbrich@rub.de.
Sarah
S
Ulbrich
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry und Pathobiochemistry, Ruhr University Bochum, 44801 Bochum, Germany. Electronic address: Joerg.Tatzelt@rub.de.
Jörg
J
Tatzelt
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany. Electronic address: cbehl@uni-mainz.de.
Christian
C
Behl
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, 55099 Mainz, Germany. Electronic address: akern@uni-mainz.de.
Andreas
A
Kern
D001343:Autophagy / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020692:rab3 GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000097573:Red Fluorescent Protein
D008164:Luminescent Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D020691:rab GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins; D000097573:Red Fluorescent Protein; C484168:RAB18 protein, human; C555465:RAB3GAP2 protein, human; C580955:RAB3GAP1 protein, human
Autophagy; Proteostasis; RAB18; RAB3GAP1; RAB3GAP2; Warburg Micro syndrome