Rabin8 suppresses autophagosome formation independently of its guanine nucleotide-exchange activity towards Rab8

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6 Citations (Scopus)

Abstract

Macroautophagy is a bulk degradation system conserved from yeast to human. In budding yeast, the guanine nucleotide-exchange factor (GEF) Sec2p is required for autophagy. We examined the role of Rabin8 (a mammalian ortholog of Sec2p) with Rab8-GEF activity in autophagy in mammalian cells. Unexpectedly, depletion of Rabin8 promoted nutrient starvation-induced autophagosome formation, indicating that Rabin8 suppresses autophagosome formation. Depletion of Rab8 did not affect autophagosome formation, and expression of a Rabin8 GEF-domain mutant reverted the Rabin8 depletion-induced increase in autophagosomes, indicating that Rabin8 suppresses autophagosome formation independently of its Rab8-GEF activity. Nuclear Dbf2-related (NDR) kinases phosphorylate Rabin8 at Ser-272. The non-phosphorylatable Rabin8-S272A mutant did not revert the Rabin8 depletion-induced increase in autophagosomes, suggesting that Ser-272 phosphorylation of Rabin8 is involved in its suppressive function in autophagy. Depletion of NDR kinases enhanced autophagosome formation and reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity, suggesting that NDR kinases suppress autophagosome formation by increasing mTORC1 activity, in addition to phosphorylating Rabin8. Expression of a C-terminal fragment of Rabin8, but not that of Sec2p, suppressed nutrient starvation-induced autophagosome formation. Thus, contrary to the stimulative role of yeast Sec2p, Rabin8 has a suppressive function in autophagy in mammalian cells through its non-conserved C-terminal region.

Original languageEnglish
Pages (from-to)139-153
Number of pages15
JournalJournal of biochemistry
Volume158
Issue number2
DOIs
Publication statusPublished - 2014 Dec 18

Keywords

  • NDR
  • Rab8
  • Rabin8
  • autophagy
  • mTORC1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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