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Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2α (P-eIF2α). Pharmacological inhibition of the eIF2α phosphatase with the small molecule sal003 maintains P-eIF2α and permits the expansion of satellite cells ex vivo. Paradoxically, P-eIF2α also increases the translation of specific mRNAs, which is mediated by P-eIF2α-dependent read-through of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2α-dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5′ UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2α-dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle.
Myosin X forms an
antiparallel dimer and moves processively on
actin bundles. How the antiparallel dimer affects the stepping mechanism
of myosin X remains elusive. Here, we generated several chimeras using
domains of myosin V and X and performed single-molecule motility assays.
We found that the chimera containing the motor domain from myosin
V and the lever arm and antiparallel coiled-coil domain from myosin
X has multiple forward step sizes and moves processively, similar
to full-length myosin X. The chimera containing the motor domain and
lever arm from myosin X and the parallel coiled-coil from myosin V
takes steps of ∼40 nm at lower ATP concentrations but was nonprocessive
at higher ATP concentrations. Furthermore, mutant myosin X with four
mutations in the antiparallel coiled-coil domain failed to dimerize
and was nonprocessive. These results imply that the antiparallel coiled-coil
domain is necessary for multiple forward step sizes of myosin X.
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