PhD Scientific Days 2020

Molecular Sciences III. Lectures

Fine-tuning of AMPK-ULK1-mTOR Regulatory Triangle is Crucial for Periodic Activation of Autophagy

Előadó neve

Holczer, Marianna, MSc

Előadó munkahelye

Department of Medical Chemistry, Molecular Biology and Pathobiochemistry

Előadó telefonszáma

+36 1 459 15 00 60178

Előadó e-mail címe

holczer.marianna@med.semmelweis-univ.hu

Az előadás címe

Fine-tuning of AMPK-ULK1-mTOR Regulatory Triangle is Crucial for Periodic Activation of Autophagy

Szerző(k) neve és munkahelye

Marianna Holczer 1, Bence Hajdú 2, Gábor Bánhegyi 3, Orsolya Kapuy 4
1,2,3,4 Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry,

Szekció

Molecular Sciences III. Lectures

Language of the presentation

Hungarian

Section, first choice

Molecular Sciences

Section, second choice

Molecular Sciences

Összefoglaló szövege

Introduction: The autophagy-dependent self-eating is tightly regulated by mTOR and AMPK kinases. AMPK promotes autophagy by phosphorylating ULK1, the key inducer of autophagosome formation, meanwhile mTOR down-regulates it under nutrient rich condition. However, the active ULK1 can inhibit both AMPK and mTOR. Interestingly, a periodic activation of ULK1 was also observed during prolonged stress.

Aims: We claim that the negative and double negative feedback loops of AMPK-mTOR-ULK1 regulatory triangle determine an accurate dynamical characteristic of autophagic process to cellular stress (such as starvation or rapamycin-induced mTOR inhibition).

Method: We approach our scientific analysis from a systems biological perspective by using both theoretical and molecular biological techniques. For molecular biological experiments HEK293T cell line is used, meanwhile the dynamical characteristic of the regulatory network is described by mathematical modelling.

Results: In our study we suppose that a delayed negative feedback loop between AMPK and ULK1 is essential to manage a proper cellular answer upon autophagy induction. By using both molecular and theoretical biological techniques, we suggest that AMPK kinase gets induced followed by ULK1 activation during prolonged starvation or rapamycin treatment, whereas active ULK1 kinase quickly down-regulates AMPK resulting in a delayed decrease in ULK1 activity. This periodic repeat of AMPK-ULK1 activation/inactivation due to the negative feedback between them generates an oscillatory activation of autophagy, as well. We demonstrate that this periodic induction of autophagy is essential to guaranty the suitable dynamical features of the control network when mTOR is down-regulated.

Conclusion: Understanding how the regulation of the cell survival with precise molecular balance of mTOR-AMPK in autophagy occurs, is highly relevant in several cellular stress related diseases (such as neurodegenerative diseases) and might help to promote advanced therapies in the near future, too.

Supported by the ÚNKP-19-3-I-SE-81 New National Excellence Program of the Ministry for Innovation and Technology.

Additional Information

Supervisor: Orsolya Kapuy-Mészáros
E-mail address: kapuy.orsolya@med.semmelweis-univ.hu

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

4074

Start

10:10

End

10:25

Authors (legacy)

Marianna Holczer 1, Bence Hajdú 2, Gábor Bánhegyi 3, Orsolya Kapuy 4
1,2,3,4 Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry,