Using the attached journal article on Eukaryotic initiation factor & JCP spotlight piece to answer the attached cell biology questions.
SPOTLIGHT
Factoring in the force: A novel role for eIF6
Darren Graham Samuel Wilson1,2 and Thomas Iskratsch1?
Recent developments in the ?eld of mechanobiology have revealed crucial interactions
between the cell and its microenvironment.
Fundamentally, the conversion of physical
forces into biochemical signals and genetic
responses, termed mechanotransduction,
governs cell behaviors including migration,
differentiation, maturation, and organogenesis (1). Central to mechanotransduction
is the cytoskeleton, comprising actin ?laments, microtubules, and intermediate ?laments. The cytoskeleton is sensitive to
chemical and mechanical alterations of the
extracellular matrix and mediates changes
to cell behavior and morphology. Physical
forces are propagated along tensed actin
cables all the way to the nucleus, where they
connect to the linker of nucleoskeleton and
cytoskeleton (LINC) complex (2).
Defective mechanosensing and transduction are implicated in major diseases,
where changes to adhesion composition,
cytoskeleton, and downstream signaling to
the nucleus ultimately interfere with appropriate gene expression. For this, several
mechanisms have been uncovered, including force-dependent chromatin decondensation, leading to long-term promoter
silencing (3); force-dependent changes to
epigenetics (4); or nuclear shuttling of
transcriptional factors. In the latter case,
recent work showed that forces on the nucleus (e.g., through the cytoskeleton) allow
opening of the nuclear pore complexes,
enabling the nuclear shuttling of the
transcriptional coactivator Yes-Associated
Protein (YAP), where it regulates gene expression, proliferation, and of particular
interest to the cardiovascular community,
cell (i.e., cardiomyocyte) regeneration (5).
Other studies suggest an essential role
for mechanical forces in regulating protein
synthesis. The translational machinery—
ribosomes and associated factors—are associated with the cytoskeleton and can localize to focal adhesions (6). Cytoskeletal
tension, which changes over space and time,
also affects which mRNAs may be recruited
over others, providing an additional layer of
complexity (6). Physical forces are paramount to the propagation of the amino acids
within the ribosomal core complex, as well
as the unwinding of mRNA structures, such
as hairpin loops (7). However, these are
likely only a fraction of the mechanisms in
the intimate relationship between mechanical forces, gene regulation, or protein
translation. It is clear that fully de?ning
these relationships is essential to unlock the
therapeutic potential required to combat
pathogenic states.
One additional layer of regulatory complexity between cellular forces and protein
synthesis is outlined in the current issue by
Keen et al. (8). Here, the authors present a
novel, noncanonical mechanism of the eukaryotic initiation factor 6 (eIF6), a stimulatory translation initiation factor that acts
downstream of insulin, or growth factors.
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