PROJECT SUMMARY/ABSTRACT
Caspases are a group of proteases most well known for their destructive role in apoptosis. While their
activation is often equated with cell death, in skeletal muscles, this does not hold true. For example, during
myogenic differentiation, caspases are activated in a transient, regulated, and reversible manner. These
proteases can also be activated chronically in Duchenne or limb-girdle muscular dystrophies. Nevertheless, very
little is known about the non-apoptotic roles of caspases in muscle formation and degeneration. By focusing on
caspase-mediated trimming of the nuclear pore complex (NPC), this K01 project will elucidate how sublethal
caspases bring about such contrasting outcomes. Caspases can proteolyze four distal subunits of the NPC,
impair nuclear export, and entrap several NES (nuclear export signal)-containing proteins, many of which have
genome regulatory functions. In Aim 1, NES-containing proteins that accumulate in the nucleus during
myogenesis and drive genome reconfiguration will be identified in an unbiased manner. In addition, a focused
study will be conducted to understand how FAK, an NES-containing focal adhesion protein that doubles as a
transcription cofactor in the nucleus, interacts with MBD2, a methyl CpG-binding protein, to de-repress myogenic
genes. In Aim 2, caspase-mediated NPC trimming in dystrophic muscles will be assessed. Given that modest
activation of caspases by ER stressors is sufficient to cause NPC trimming and nuclear export shutdown in
myotubes, the NPC in dystrophic muscles will be similarly modified and dysfunctional. Therefore, a proteome-
wide search will be performed to identify proteins whose nuclear levels are abnormally high in dystrophic
myonuclei and have potential to induce genome dysregulation.
In short, by dissecting the antagonistic pleiotropy of the caspase-NPC-nuclear export axis, this proposal
aims to provide a foundation for new therapeutic approaches that promote muscular health in both healthy
individuals and muscular dystrophy patients. This research combines the expertise of the Martin Hetzer lab (the
Salk Institute) in the NPC and that of the Lorenzo Puri lab (Sanford-Burnham-Prebys) in muscle biology. Dr.
Cho’s long-term goal is to lead a research group that studies nuclear proteome and proteases in the context of
myogenesis and muscular dystrophies. K01 award will provide him the stability, networking opportunity, and
confidence to develop into a young leader in the field of muscle biology who is proficient in both reductionist and
systems approaches.