pt9b00052_si_002.xlsx (5.13 MB)
Genome-Wide RNAi Screen Identifies Regulators of Cardiomyocyte Necrosis
dataset
posted on 2019-09-16, 20:17 authored by Zhaokang Cheng, Matthew Combs, Qiang Zhu, Peng Xia, Zachary Opheim, Joel Parker, Christopher P. Mack, Joan M. TaylorRegulation
of cellular death is central to nearly all physiological
routines and is dysregulated in virtually all diseases. Cell death
occurs by two major processes, necrosis which culminates in a pervasive
inflammatory response and apoptosis which is largely immunologically
inert. As necrosis has long been considered an accidental, unregulated
form of cellular death that occurred in response to a harsh environmental
stimulus, it was largely ignored as a clinical target. However, recent
elegant studies suggest that certain forms of necrosis can be reprogrammed.
However, scant little is known about the molecules and pathways that
orchestrate calcium-overload-induced necrosis, a main mediator of
ischemia/reperfusion (IR)-induced cardiomyocyte cell death. To rectify
this critical gap in our knowledge, we performed a novel genome-wide
siRNA screen to identify modulators of calcium-induced necrosis in
human muscle cells. Our screen identified multiple molecular circuitries
that either enhance or inhibit this process, including lysosomal calcium
channel TPCN1, mitophagy mediatorTOMM7, Ran-binding protein RanBP9,
Histone deacetylase HDAC2, chemokine CCL11, and the Arp2/3 complex
regulator glia maturation factor-γ (GMFG). Notably, a number
of druggable enzymes were identified, including the proteasome β5
subunit (encoded by PSMB5 gene), which controls the proteasomal chymotrypsin-like
peptidase activity. Such findings open up the possibility for the
discovery of pharmacological interventions that could provide therapeutic
benefits to patients affected by myriad disorders characterized by
excessive (or too little) necrotic cell loss, including but not limited
to IR injury in the heart and kidney, chronic neurodegenerative disorders,
muscular dystrophies, sepsis, and cancers.
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CCLnovel genome-wide siRNA screendruggable enzymesSuch findingsIR injurycalcium-overload-induced necrosiscalcium-induced necrosisregulator glia maturation factor -γHDACTPCNproteasome β5 subunitGMFGcell lossmuscle cellsGenome-Wide RNAi Screen Identifies Regulatorsproteasomal chymotrypsin-like peptidase activityneurodegenerative disordersresponsecell deathCardiomyocyte Necrosis RegulationPSMB
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