Subcellular Redox Targeting: Bridging in Vitro and in Vivo Chemical Biology

Long, Marcus J. C.; Poganik, Jesse R.; Ghosh, Souradyuti; Aye, Yimon

doi:10.1021/acschembio.6b01148

Cited by 26 publications

(44 citation statements)

References 176 publications

(347 reference statements)

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“…We recently developed T-REX, a method that interrogates how non-enzymatic redox modification affects temporal function and signaling trajectories in response to a chemical signal input targeted at a specific protein of interest (POI) (Figure 1A) (Fang, et al, 2013; Lin, et al, 2015; Parvez, et al, 2015; Parvez, et al, 2016; Long, et al, 2017a; Long, et al, 2016; Long, et al, 2017b). T-REX uses a bio-inert photocaged precursor to a specific reactive signal.…”

Section: Introductionmentioning

confidence: 99%

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Long

Lin

Parvez

et al. 2017

Cell Chemical Biology

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Summary Simultaneous hyperactivation of Wnt and antioxidant response (AR) are often observed during oncogenesis. However, it remains unclear how the β-catenin-driven Wnt and the Nrf2-driven AR mutually regulate each other. The situation is compounded because many players in these two pathways are redox-sensors, rendering bolus-redox-signal-dosing methods uninformative. Herein we examine the ramifications of single-protein-target-specific AR-upregulation in various knockdown lines. Our data document that Nrf2/AR strongly inhibits β-catenin/Wnt. The magnitude and mechanism of this negative regulation are dependent on the direct interaction between β-catenin-N-terminus and β-TrCP1 (an antagonist of both Nrf2 and β-catenin), and independent of binding between Nrf2 and β-TrCP1. Intriguingly, β-catenin positively regulates AR. Because AR is a negative regulator of Wnt regardless of β-catenin-N-terminus, this switch of function is likely sufficient to establish a new Wnt/AR equilibrium during tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Long

Lin

Parvez

et al. 2017

Cell Chemical Biology

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113

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“…16 Unfortunately, many of these protocols are restricted to cultured cells and/or offer limited spatiotemporal resolution. Many also require extensive downstream processing.…”

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confidence: 99%

“…19,20 Indeed, the synergy between biochemistry/chemical biology and genetics/cell biology is arguably magnified in redox signaling. 15,16,21,22 This is because many RES are toxic at elevated concentrations and promiscuous, engage with specific proteins without mediator enzymes, and can be converted to numerous products. 11 Thus, genetic approaches alone cannot address precision mapping of nonenzymatic RES signal input on a single target to specific signaling output.…”

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confidence: 99%

Precision Electrophile Tagging in Caenorhabditis elegans

et al. 2017

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Adduction of an electrophile to privileged sensor proteins and the resulting phenotypically dominant responses are increasingly appreciated as being essential for metazoan health. Functional similarities between the biological electrophiles and electrophilic pharmacophores commonly found in covalent drugs further fortify the translational relevance of these small-molecule signals. Genetically encodable or small-molecule-based fluorescent reporters and redox proteomics have revolutionized the observation and profiling of cellular redox states and electrophile–sensor proteins, respectively. However, precision mapping between specific redox-modified targets and specific responses has only recently begun to be addressed, and systems tractable to both genetic manipulation and on-target redox signaling in vivo remain largely limited. Here we engineer transgenic Caenorhabditis elegans expressing functional HaloTagged fusion proteins and use this system to develop a generalizable light-controlled approach to tagging a prototypical electrophile–sensor protein with native electrophiles in vivo. The method circumvents issues associated with low uptake/distribution and toxicity/promiscuity. Given the validated success of C. elegans in aging studies, this optimized platform offers a new lens with which to scrutinize how on-target electrophile signaling influences redox-dependent life span regulation.

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“…However, in light of seminal studies by many laboratories on ROS‐signaling and our own work with on‐target RES‐signaling discussed below, it is likely that phenotypically‐relevant outputs may occur at low occupancy. Furthermore, the competitive ABPP‐method intrinsically assumes that the targets of iodoacetamide (the reporter electrophile) and the RES are the same (although, chemically, iodoacetamide is an sp 3 ‐hybridized electrophile, whereas Michael‐acceptor‐based RES—the largest class of RES in mammalian systems—are sp 2 ‐hybridized; thus their reactivity and “nucleophile–electrophile matching” likely differ).…”

Section: Thresholds That Must Be Passed To Establish Res As a Biologimentioning

confidence: 99%

Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators

2018

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Precision cell signaling activities of reactive electrophilic species (RES) are arguably among the most poorly-understood means to transmit biological messages. Latest research implicates native RES to be a chemically-distinct subset of endogenous redox signals that influence cell decision making through non-enzyme-assisted modifications of specific proteins. Yet, fundamental questions remain regarding the role of RES as bona fide second messengers. Here, we lay out three sets of criteria we feel need to be met for RES to be considered as true cellular signals that directly mediate information transfer by modifying "first-responding" sensor proteins. We critically assess the available evidence and define the extent to which each criterion has been fulfilled. Finally, we offer some ideas on the future trajectories of the electrophile signaling field taking inspiration from work that has been done to understand canonical signaling mediators. Also see the video abstract here: https://youtu.be/rG7o0clVP0c.

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Subcellular Redox Targeting: Bridging in Vitro and in Vivo Chemical Biology

Cited by 26 publications

References 176 publications

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

β-TrCP1 Is a Vacillatory Regulator of Wnt Signaling

Precision Electrophile Tagging in Caenorhabditis elegans

Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators

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