From Yeast to Human Cells and Disease: 1) Regulation and Coordination of Trafficking Inside Cells: secretion, endocytosis and autophagy; 2) Neurological Disorders (neurodevelopmental and neurodegeneration)-associated mutations in highly conserved genes

Regulation of Intracellular Trafficking by Molecular Switches and Cascades

Our research is aimed at understanding a basic cellular process, trafficking inside cells, in which proteins and membranes are shuttled between cellular organelles. This process is required for proper functioning of all cells, and therefore for every system of the human body. Elucidation of the mechanisms that regulate trafficking inside cells is relevant to a variety of diseases caused by impaired transport of substances that are either essential, such as insulin in diabetes, growth-factor receptors in cancer and CFTR in cystic fibrosis, or detrimental, such as -amyloid in Alzheimer’s disease.

The conserved molecular switches Ypt (in yeast) and Rab (in humans) GTPases have emerged as key regulators of individual transport steps. They are activated by guanine-nucleotide exchange factors (GEFs), and when in the active form, they interact with downstream effectors that mediate vesicular transport. Our long-term goal is to elucidate how Ypt/Rab GTPases together with their GEFs and effectors coordinate multiple transport steps and pathways.

To address these complicated issues, we are using yeast as a model because it allows utilizing sophisticated genetic approaches in combination with molecular and cellular methods. Furthermore, the relatively small number of players (e.g., 11 Ypts in yeast versus ~70 Rabs in humans) and the resultant simplified interaction networks make yeast an excellent model for studying the coordination of transport steps. Currently, we are studying the role of Ypt GTPases in secretion and in the cellular recycling pathway autophagy.

Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence. Gyurkovska V, Murtazina R, Zhao SF, Shikano S, Okamoto Y, Segev N. Life Sci Alliance. 2023 Feb 13;6(5):e202201810

Characterization of constitutive ER-phagy of excess membrane proteins. Lipatova Z, Gyurkovska V, Zhao SF, Segev N. PLoS Genet. 2020 Dec 4;16(12):e1009255. doi: 10.1371/journal.pgen.1009255. eCollection 2020 Dec.

Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, Murtazina R, Gyurkovska V, Pehlivan D, Mitani T, Gezdirici A, Antony J, Collins F, Willis MJH, Coban Akdemir ZH, Liu P, Punetha J, Hunter JV, Jhangiani SN, Fatih JM, Rosenfeld JA, Posey JE, Gibbs RA, Karaca E, Massey S, Ranasinghe TG, Sleiman P, Troedson C, Lupski JR, Sacher M, Segev N, Hakonarson H, Christodoulou J. Brain. 2020 Jan 1;143(1):112-130. (Co-corresponding author)

Rab5-dependent autophagosome closure by ESCRT. Zhou F, Wu Z, Zhao M, Murtazina R, Cai J, Zhang A, Li R, Sun D, Li W, Zhao L, Li Q, Zhu J, Cong X, Zhou Y, Xie Z, Gyurkovska V, Li L, Huang X, Xue Y, Chen L, Xu H, Xu H, Liang Y, Segev N. J Cell Biol. 2019 Jun 3;218(6):1908-1927.

A Rab5 GTPase module is important for autophagosome closure. Zhou F, Zou S, Chen Y, Lipatova Z, Sun D, Zhu X, Li R, Wu Z, You W, Cong X, Zhou Y, Xie Z, Gyurkovska V, Liu Y, Li Q, Li W, Cheng J, Liang Y, Segev N. PLoS Genet. 2017 Sep 21;13(9)

Regulation of Golgi Cisternal Progression by Ypt/Rab GTPases. Kim JJ, Lipatova Z, Majumdar U, Segev N. Dev Cell. 2016 Feb 22;36(4):440-52.

A Role for Macro-ER-Phagy in ER Quality Control. Lipatova Z, Segev N. PLoS Genet. 2015 Jul 16;11(7):e1005390.

Newer Methods Drive Recent Insights into Rab GTPase Biology: An Overview. Li G, Segev N. Methods Mol Biol. 2021;2293:1-18.

TRAPPing a neurological disorder: from yeast to humans. Lipatova Z, Van Bergen N, Stanga D, Sacher M, Christodoulou J, Segev N. Autophagy. 2020 May;16(5):965-966.

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi. Lipatova Z, Segev N. FEBS Lett. 2019 Sep;593(17).

TRAPP Complexes in Secretion and Autophagy. Kim JJ, Lipatova Z, Segev N. Front Cell Dev Biol. 2016 Mar 30;4:20.

Ypt/Rab GTPases: principles learned from yeast. Lipatova Z, Hain AU, Nazarko VY, Segev N. Crit Rev Biochem Mol Biol. 2015;50(3):203-11.

Rab GTPases: Methods and Protocols (Methods in Molecular Biology, 2293) Guangpu Li and Nava Segev, Editors (2021), Publisher: Springer

Rab GTPases and Membrane Trafficking Guangpu Li, Nava Segev, Editors (2018), Publisher: Bentham Science

UIC University Scholar (2016-2019)