Htm1p: getting a “sugar-handle” on misfolded proteins

نویسنده

  • Caitlin Sedwick
چکیده

Mutations in the nuclear intermediate fi lament lamin A/C (LMNA) gene are associated with Emery-Dreifuss muscular dystrophy, but cause the disease by unknown mechanisms. Méjat et al. show that one mechanism involves the disruption of neuromuscular junctions. Muscle fi ber cells contain hundreds of nuclei. In normal fi bers, several nuclei cluster together under the cell membrane at sites of neuronal contact. These postsynaptic nuclei synthesize the components of the neuromuscular junction that specify the overlying membrane as the target site for innervation. The authors found that LMNA-defi cient animals (including those with a point mutation in LMNA that in humans can cause Emery-Dreifuss disease) failed to position nuclei into these postsynaptic clusters. This prevented the proper organization of the neuromuscular junction and disrupted muscle fi ber innervation, says author Alexandre Méjat. The authors showed that either loss or mutation of LMNA disrupted nuclear positioning by causing the mislocalization of two other proteins: Nesprin-1, which spans the outer nuclear membrane and anchors nuclei to the actin cytoskeleton, and SUN2, which spans the inner nuclear membrane, linking Nesprin to lamin A/C. Although lamin A/C is ubiquitously expressed, LMNA defects specifi cally affected striated and skeletal muscle because Nesprin-1 and SUN2 are highly expressed in these tissues. Samples from Emery-Dreifuss muscular dystrophy patients exhibit similar hallmarks of skeletal muscle functional denervation, suggesting the authors are on the right track. It takes two to par ty with chromatin Xu et al. have discovered that two sustained signals combine to support milk production by mammary cells. In vivo, mammary epithelial cells synthesize milk proteins when stimulated by the hormone prolactin. Yet, when these cells are cultured on fl at, plastic dishes they do not make milk proteins even when prolactin is added to the cultures. The authors found that the cells on plastic became polarized with separate apical and basolateral surfaces. The prolactin receptor is present on the cells, but is localized on their basolateral side—attached to the dish—and thus cannot be accessed by prolactin applied to the apical surface. Xu et al. showed that if prolactin was applied basolaterally to cells on plastic it could activate STAT5, the transcription factor that controls the expression of milk proteins—but this signal was transient and insuffi cient to support milk protein production. A second signal was required to achieve the sustained STAT5 activation and subsequent chromatin rearrangements that make milk genes accessible for transcription. This signal …

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عنوان ژورنال:
  • The Journal of Cell Biology

دوره 184  شماره 

صفحات  -

تاریخ انتشار 2009