Engineering metabolite-responsive transcriptional factors to sense small molecules in eukaryotes: current state and perspectives
Loading...
Author/Creator
Author/Creator ORCID
Date
2019-03-26
Type of Work
Department
Program
Citation of Original Publication
Xia Wan, Monireh Marsafari and Peng Xu, Engineering metabolite-responsive transcriptional factors to sense small molecules in eukaryotes: current state and perspectives, Microbial Cell Factories ,2019, 18:61, https://doi.org/10.1186/s12934-019-1111-3
Rights
This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
Attribution 4.0 International (CC BY 4.0)
Attribution 4.0 International (CC BY 4.0)
Abstract
Nature has evolved exquisite sensing mechanisms to detect cellular and environmental signals surrounding living
organisms. These biosensors have been widely used to sense small molecules, detect environmental cues and diagnose
disease markers. Metabolic engineers and synthetic biologists have been able to exploit metabolites-responsive
transcriptional factors (MRTFs) as basic tools to rewire cell metabolism, reprogram cellular activity as well as boost
cell’s productivity. This is commonly achieved by integrating sensor-actuator systems with biocatalytic functions and
dynamically allocating cellular resources to drive carbon flux toward the target pathway. Up to date, most of identified
MRTFs are derived from bacteria. As an endeavor to advance intelligent biomanufacturing in yeast cell factory, we will
summarize the opportunities and challenges to transfer the bacteria-derived MRTFs to expand the small-molecule
sensing capability in eukaryotic cells. We will discuss the design principles underlying MRTF-based biosensors in
eukaryotic cells, including the choice of reliable reporters and the characterization tools to minimize background
noise, strategies to tune the sensor dynamic range, sensitivity and specificity, as well as the criteria to engineer activator
and repressor-based biosensors. Due to the physical separation of transcription and protein expression in eukaryotes,
we argue that nuclear import/export mechanism of MRTFs across the nuclear membrane plays a critical role in
regulating the MRTF sensor dynamics. Precisely-controlled MRTF response will allow us to repurpose the vast majority
of transcriptional factors as molecular switches to achieve temporal or spatial gene expression in eukaryotes. Uncovering
this knowledge will inform us fundamental design principles to deliver robust cell factories and enable the
design of reprogrammable and predictable biological systems for intelligent biomanufacturing, smart therapeutics or
precision medicine in the foreseeable future.