Precision Electrophile Tagging in <i>Caenorhabditis
elegans</i>
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Abstract
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 <i>Caenorhabditis elegans</i> 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 <i>C.
elegans</i> 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