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PreprintCited by 10PI3K/AKT/mTOR signaling in cancerFungal and yeast genetics researchAutophagy in Disease and Therapy

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Conserved Pib2 regions have distinct roles in TORC1 regulation at the vacuole

Open access
Troutman, Kayla K., Varlakhanova, Natalia V., Tornabene, Bryan A., Ramachandran, Rajesh, Ford, Marijn G.J.·2022·Journal of Cell Science
DOI 10.1101/2022.03.04.483060PMC PMC9584352

Preprint — published as 10.1242/jcs.259994 · Paper page

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Abstract

TORC1 is a critical controller of cell growth in eukaryotes. In yeast, the presence of nutrients is signaled to TORC1 by several upstream regulatory sensors that together coordinate TORC1 activity. TORC1 localizes to both vacuolar and endosomal membranes, where differential signaling occurs. This localization is mimicked by Pib2, a key upstream TORC1 regulator that is essential for TORC1 reactivation after nutrient starvation or pharmacological inhibition. Pib2 has both positive and negative effects on TORC1 activity, but the mechanisms remain poorly understood. Here, we pinpoint the Pib2 inhibitory function on TORC1 to residues within short, conserved N-terminal regions. We also show that Pib2 C-terminal regions, helical region E and tail, are essential for TORC1 reactivation. Further, the Pib2 FYVE domain is essential for vacuolar localization, however, it is surprisingly unnecessary for recovery from rapamycin exposure. Using chimeric Pib2 targeting constructs, we show that endosomal localization is not necessary for TORC1 reactivation and cell growth after rapamycin treatment. Thus, a comprehensive molecular dissection of Pib2 demonstrates that each of its conserved regions differentially contribute to Pib2 regulation of TORC1 activity.

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Metadata

Authors
Troutman, K. K., Varlakhanova, N. V., Tornabene, B. A., Ramachandran, R., & Ford, M. G. J.
Affiliations
  • University of Pittsburgh (US)
  • Case Western Reserve University (US)
Corresponding author
Ford, Marijn G.J.
ORCID
Venue
Journal of Cell Science
Publisher
openRxiv
Published
2022-03-04
Volume
135
Issue
18
ISSN
0021-9533 (ISSN-L)
DOI
10.1101/2022.03.04.483060
PMC
PMC9584352
OpenAlex
W4293171180
Cited by
10
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 1
FWCI
0.57
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Cell Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • University of Pittsburgh
  • National Institutes of Health (1s10od023481-01)
  • National Cancer Institute (P30CA047904)
  • National Institute of General Medical Sciences (R01GM121583, T32GM133353, R35GM139546)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
TORC1, TOR signaling, nutrient signaling, vacuoles, endosomes, FYVE domain, rapamycin, nutrient deprivation, cell growth regulation, Saccharomyces cerevisiae
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Saccharomyces cerevisiae, Vacuoles, Sirolimus, Saccharomyces cerevisiae Proteins, Apoptosis Regulatory Proteins

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