Pib2 Explained

Phosphatidylinositol 3-phosphate-binding protein 2
Organism:Saccharomyces cerevisiae
Taxid:559292
Symbol:PIB2
Entrezgene:852861
Homologene:39059
Refseqmrna:NM_001180888.3
Refseqprotein:NP_011492.3
Uniprot:P53191
Chromosome:VII
Entrezchromosome:NC_001139.9
Genloc Start:449910
Genloc End:452389

Phosphatidylinositol 3-phosphate-binding protein 2 (Pib2) is a yeast protein involved in the regulation of TORC1 signaling[1] [2] [3] [4] [5] and lysosomal membrane permeabilization. It is essential for the reactivation of TORC1 following exposure to rapamycin or nutrient starvation.

Discovery

Pib2 was first identified as a FYVE domain-containing protein able to bind phosphatidylinositol 3-phosphate (PI3P).[6] Pib2 was later identified in a screen for rapamycin sensitivity, along with several other TORC1 regulatory proteins (including Ego1, Gtr1, Gtr2, and other key TORC1 related proteins).[7]

Structure

Pib2 is a 70.6 kDa protein with 635 amino acids (Uniprot - P53191). Pib2 has 5 weakly conserved motifs among fungi and 2 universally conserved motifs. The partially conserved motifs are found in the N-terminal region of the protein and are generally referred to as regions A-E The universally conserved motifs include a phosphatidylinositol-3-phosphate (PI3P)-binding FYVE domain, and a short tail motif at the C-terminus.

Mammalian homologs

Pib2 has 2 mammalian homologs, Phafin1 (also known as LAPF or PLEKHF1) and Phafin2 (EAPF or PLEKHF2). The phafin proteins each have a PH (pleckstrin homology) domain and FYVE domain. Phafin1 also has a tail motif similar to that of Pib2. These proteins have not been shown to be involved in the regulation of mammalian TORC1 signaling but have been shown to be involved in related processes.[8] [9]

Function

TORC1 regulation

In Saccharomyces cerevisiae, Pib2 has been shown to be involved in regulating TORC1 signaling. Pib2 is found at the yeast vacuole and endosomes.[10] The PI3P binding FYVE domain of Pib2 is key for this localization. Pib2 also interacts with some TORC1 components, including Kog1 and Tor1, and has been shown to be necessary for TORC1 reactivation following inhibition by rapamycin or nutrient starvation. Additionally, Pib2 is essential for TORC1 reactivation by stimulation with leucine and glutamine.

In terms of TORC1 reactivation, it has been observed that Pib2 can have both a positive and negative effect. The C-terminus of Pib2 is key for TORC1 reactivation, whereas the N-terminal region has an inhibitory effect on TORC1 reactivation.

Lysosomal membrane permeabilization

Lysosomal membrane permeabilization (LMP) is a process which is important for inducing cell death in a range of animals and plants.[11] [12] [13] [14] LMP also occurs in Saccharomyces cerevisiae during sporulation.[15] Pib2 has been implicated in the regulation of this process in stressed yeast through the promotion of TORC1 activity.

Notes and References

  1. Kim A, Cunningham KW . A LAPF/phafin1-like protein regulates TORC1 and lysosomal membrane permeabilization in response to endoplasmic reticulum membrane stress . Molecular Biology of the Cell . 26 . 25 . 4631–45 . December 2015 . 26510498 . 4678020 . 10.1091/mbc.E15-08-0581 . Glick BS .
  2. Varlakhanova NV, Mihalevic MJ, Bernstein KA, Ford MG . Pib2 and the EGO complex are both required for activation of TORC1 . Journal of Cell Science . 130 . 22 . 3878–3890 . November 2017 . 28993463 . 5702048 . 10.1242/jcs.207910 .
  3. Michel AH, Hatakeyama R, Kimmig P, Arter M, Peter M, Matos J, De Virgilio C, Kornmann B . 6 . Functional mapping of yeast genomes by saturated transposition . eLife . 6 . e23570 . May 2017 . 28481201 . 5466422 . 10.7554/eLife.23570 . free .
  4. Ukai H, Araki Y, Kira S, Oikawa Y, May AI, Noda T . Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane . PLOS Genetics . 14 . 4 . e1007334 . April 2018 . 29698392 . 5919408 . 10.1371/journal.pgen.1007334 . free .
  5. Sullivan A, Wallace RL, Wellington R, Luo X, Capaldi AP . Multilayered regulation of TORC1-body formation in budding yeast . Molecular Biology of the Cell . 30 . 3 . 400–410 . February 2019 . 30485160 . 10.1091/mbc.E18-05-0297 . 6589571 . Luo K .
  6. Shin ME, Ogburn KD, Varban OA, Gilbert PM, Burd CG . FYVE domain targets Pib1p ubiquitin ligase to endosome and vacuolar membranes . The Journal of Biological Chemistry . 276 . 44 . 41388–93 . November 2001 . 11526110 . 10.1074/jbc.M105665200 . 19257611 . free .
  7. Parsons AB, Brost RL, Ding H, Li Z, Zhang C, Sheikh B, Brown GW, Kane PM, Hughes TR, Boone C . 6 . Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways . Nature Biotechnology . 22 . 1 . 62–9 . January 2004 . 14661025 . 10.1038/nbt919 . 10606058 .
  8. Chen W, Li N, Chen T, Han Y, Li C, Wang Y, He W, Zhang L, Wan T, Cao X . 6 . The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway . The Journal of Biological Chemistry . 280 . 49 . 40985–95 . December 2005 . 16188880 . 10.1074/jbc.m502190200 . 13634278 . free .
  9. Matsuda-Lennikov M, Suizu F, Hirata N, Hashimoto M, Kimura K, Nagamine T, Fujioka Y, Ohba Y, Iwanaga T, Noguchi M . 6 . Lysosomal interaction of Akt with Phafin2: a critical step in the induction of autophagy . PLOS ONE . 9 . 1 . e79795 . 2014-01-08 . 24416124 . 3885392 . 10.1371/journal.pone.0079795 . 2014PLoSO...979795M . Chiorini JA . free .
  10. Hatakeyama R, Péli-Gulli MP, Hu Z, Jaquenoud M, Garcia Osuna GM, Sardu A, Dengjel J, De Virgilio C . 6 . Spatially Distinct Pools of TORC1 Balance Protein Homeostasis . Molecular Cell . 73 . 2 . 325–338.e8 . January 2019 . 30527664 . 10.1016/j.molcel.2018.10.040 . free .
  11. Boya P, Kroemer G . Lysosomal membrane permeabilization in cell death . Oncogene . 27 . 50 . 6434–51 . October 2008 . 18955971 . 10.1038/onc.2008.310 . 21635483 . free . 10261/59040 . free .
  12. Mrschtik M, Ryan KM . Lysosomal proteins in cell death and autophagy . The FEBS Journal . 282 . 10 . 1858–70 . May 2015 . 25735653 . 10.1111/febs.13253 . 11609431 . free .
  13. van Doorn WG . Classes of programmed cell death in plants, compared to those in animals . Journal of Experimental Botany . 62 . 14 . 4749–61 . October 2011 . 21778180 . 10.1093/jxb/err196 . free .
  14. Hatsugai N, Yamada K, Goto-Yamada S, Hara-Nishimura I . Vacuolar processing enzyme in plant programmed cell death . Frontiers in Plant Science . 6 . 234 . 2015 . 25914711 . 4390986 . 10.3389/fpls.2015.00234 . free .
  15. Eastwood MD, Cheung SW, Meneghini MD . Programmed nuclear destruction in yeast: self-eating by vacuolar lysis . Autophagy . 9 . 2 . 263–5 . February 2013 . 23187615 . 3552897 . 10.4161/auto.22881 .