Abstract
Differentiation of secretory cells leads to sharp increases in protein synthesis, challenging endoplasmic reticulum (ER) proteostasis. Anticipatory activation of the unfolded protein response (UPR) prepares cells for the onset of secretory function by expanding the ER size and folding capacity. How cells ensure that the repertoire of induced chaperones matches their postdifferentiation folding needs is not well understood. We find that during differentiation of stem-like seam cells, a typical UPR target, the Caenorhabditis elegans immunoglobulin heavy chain-binding protein (BiP) homologue Heat-Shock Protein 4 (HSP-4), is selectively induced in alae-secreting daughter cells but is repressed in hypodermal daughter cells. Surprisingly, this lineage-dependent induction bypasses the requirement for UPR signaling. Instead, its induction in alae-secreting cells is controlled by a specific developmental program, while its repression in the hypodermal-fated cells requires a transcriptional regulator B-Lymphocyte–Induced Maturation Protein 1 (BLMP-1/BLIMP1), involved in differentiation of mammalian secretory cells. The HSP-4 induction is anticipatory and is required for the integrity of secreted alae. Thus, differentiation programs can directly control a broad-specificity chaperone that is normally stress dependent to ensure the integrity of secreted proteins.
Highlights
Cellular identity is largely defined by the proteins expressed in the cell or cellular proteome, whose functionality depends on successful folding, localization, and functional maintenance of expressed proteins
Using Caenorhabditis elegans, we find that a chaperone binding protein (BiP)/HSP-4, which is usually induced in most cells by stress, is selectively induced during differentiation of stem cells into the alae-secreting cells while being repressed in their sister lineage, the hypodermal cells
We find that induction of this chaperone is independent of the known endoplasmic reticulum (ER) stress pathways, while its repression requires a known regulator of development in mammals, BLIMP1/BLMP-1
Summary
Cellular identity is largely defined by the proteins expressed in the cell or cellular proteome, whose functionality depends on successful folding, localization, and functional maintenance of expressed proteins. An early example of this was shown during differentiation of a B-cell line into antibody-secreting cells: while expression of the majority of ER proteins, including the Heat Shock Protein 70 (HSP70)-family chaperone BiP, increased in proportion to the expansion of ER size, a small subset of ER proteins was preferentially up-regulated, resulting in their increased local concentration within the ER, presumably to support immunoglobulin folding and secretion [8]. How this selective up-regulation is achieved, and whether it requires the UPR machinery, is not well understood
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