The signaling axis of Rac1-TFEB regulates autophagy and tumorigenesis.

Abstract:

:Macroautophagy (hereafter referred to as autophagy) plays essential roles in cellular and organismal homeostasis. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis. It is not fully understood how the function of TFEB in autophagy pathway is regulated. Here, we show that Rac1 GTPase is a negative modulator of autophagy by targeting TFEB. Mechanistically, Rac1 reduces autophagy flux by repressing the expressing of autophagy genes. Further investigation revealed that under nutrient-rich conditions, mammalian target of rapamycin (mTOR) phosphorylates TFEB to facilitate the interaction between Rac1 and TFEB. Biochemical dissection uncovered that guanosine 5'-triphosphate (GTP)-bound form of Rac1 selectively interacts with phosphorylated TFEB. This inhibitory interaction prevents the dephosphorylation and nucleus translocation of TFEB, which hampers the transcriptional activation of autophagy-related genes. Furthermore, Rac1-TFEB axis appeared to be important for tumorigenesis, as overexpression of dephosphorylated mutant of TFEB was able to delay the tumor growth driven by Rac1 overexpression. Together, this study not only elucidates a previously uncharacterized autophagy regulation mechanism involving Rac1 and TFEB under physiological and pathological conditions but also suggests a strategy to treat cancers that are driven by Rac1 overexpression.

journal_name

Anticancer Drugs

journal_title

Anti-cancer drugs

authors

Ma L,Ma Y,Zhang Z,Wang Q,Liu X

doi

10.1097/CAD.0000000000000816

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

1031-1037

issue

10

eissn

0959-4973

issn

1473-5741

journal_volume

30

pub_type

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