Editors' ChoiceCell Biology

New connections: Protein trafficking for strong bones and teeth

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Sci. Signal.  07 Feb 2017:
Vol. 10, Issue 465, eaam8579
DOI: 10.1126/scisignal.aam8579

Distinct mechanisms of dysregulated protein secretion result in weak bones or teeth.

The bone matrix and tooth enamel are the hardest substances in the body, and both are formed through the mineralization of proteins secreted by osteoblasts and ameloblasts, respectively. One of the primary components of the bone matrix is collagen, which provides strength, as well as acts as a substrate for mineralization. Amelogenin is the main extracellular matrix protein secreted by ameloblasts and is important for both the inclusion of minerals and the proper structure of tooth enamel. Defects in the secretion or structure of these extracellular matrices compromise the strength and durability of the tissues. Two studies reveal distinct mechanisms of secretory dysregulation that affect proper mineralization of these tissues. Zhao et al. found that the trimeric intracellular cation channel Tric-b, which localizes to the endoplasmic reticulum (ER), was important to secretion of collagen by osteoblasts in mice. Mutations in TMEM38b, the human homolog of Tric-b, are associated with osteogenesis imperfecta (OI), a group of inherited disorders characterized by brittle bones. Similar to OI patients, the bones of mice lacking Tric-b were less mineralized and more fragile than bones from wild-type mice. The osteoblasts of Tric-b knockout mice produced collagen, but the collagen accumulated inside the cells instead of being secreted. These osteoblasts exhibited morphological and biochemical markers of ER stress, implying that Tric-b was required to maintain ER homeostasis, which is critical for this organelle’s ability to process and secrete the large amounts of collagen required for proper bone matrix formation. Cantù et al. found that several proteins best known for acting as transcriptional cofactors also functioned in the cytoplasm to promote the proper development of tooth enamel, likely by affecting the trafficking or secretion of tooth enamel proteins. In the nucleus, Bcl9, Bcl9l, Pygo1, and Pygo2 interact with the Wnt-regulated protein β-catenin to control gene expression. Although Wnt/β-catenin signaling is required for the earliest steps of tooth development, mice lacking both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in epithelial cells developed teeth, but the tooth enamel was structurally disorganized and exhibited reduced iron content compared to control mice. These phenotypes are similar to those of humans with amelogenesis imperfecta (AI), a group of inherited disorders in which mutations in any one of several enamel proteins cause defects in enamel development. Bcl9, Bcl9l, and Pygo2 localized to the region of ameloblasts from which proteins are secreted, and Bcl9 interacted with amelogenin and with proteins involved in exocytosis and vesicular trafficking, also indicating that these proteins function in the secretory pathway. These studies highlight the critical role of the trafficking and secretory machinery in the development of strong bones and teeth, and Cantù et al. reveal nontranscriptional roles for proteins classified as transcriptional coregulators.

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