TY  - JOUR
A1  - Putyrski, Mateusz
A1  - Vakhrusheva, Olesya
A1  - Bonn, Florian
A1  - Guntur, Suchithra
A1  - Vorobyov, Andrew
A1  - Brandts, Christian Hubertus
A1  - Đikić, Ivan
A1  - Ernst, Andreas
T1  - Disrupting the LC3 interaction region (LIR) binding of selective autophagy receptors sensitizes AML cell lines to cytarabine
T2  - Frontiers in cell and developmental biology
N2  - Short linear motifs (SLiMs) located in disordered regions of multidomain proteins are important for the organization of protein–protein interaction networks. By dynamic association with their binding partners, SLiMs enable assembly of multiprotein complexes, pivotal for the regulation of various aspects of cell biology in higher organisms. Despite their importance, there is a paucity of molecular tools to study SLiMs of endogenous proteins in live cells. LC3 interacting regions (LIRs), being quintessential for orchestrating diverse stages of autophagy, are a prominent example of SLiMs and mediate binding to the ubiquitin-like LC3/GABARAP family of proteins. The role of LIRs ranges from the posttranslational processing of their binding partners at early stages of autophagy to the binding of selective autophagy receptors (SARs) to the autophagosome. In order to generate tools to study LIRs in cells, we engineered high affinity binders of LIR motifs of three archetypical SARs: OPTN, p62, and NDP52. In an array of in vitro and cellular assays, the engineered binders were shown to have greatly improved affinity and specificity when compared with the endogenous LC3/GABARAP family of proteins, thus providing a unique possibility for modulating LIR interactions in living systems. We exploited these novel tools to study the impact of LIR inhibition on the fitness and the responsiveness to cytarabine treatment of THP-1 cells – a model for studying acute myeloid leukemia (AML). Our results demonstrate that inhibition of LIR of a single autophagy receptor is insufficient to sensitize the cells to cytarabine, while simultaneous inhibition of three LIR motifs in three distinct SARs reduces the IC50 of the chemotherapeutic.
KW  - phage display
KW  - selective autophagy receptor
KW  - LIR interaction,
KW  - cytarabin
KW  - AML – acute myeloid leukemia
KW  - inhibitors
KW  - short linear motifs (SLiMs)
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53339
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-533390
N1  - © 2020 Putyrski, Vakhrusheva, Bonn, Guntur, Vorobyov, Brandts, Dikic and Ernst. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 8
IS  - 208
PB  - Frontiers Research Foundation
CY  - Lausanne
ER  -