HSP-4/BiP expression in secretory cells is regulated by a developmental program and not by the unfolded protein response

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.

Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan ofCaenorhabditis elegansvia DAF-16 and HSF-1

“…Heat shock proteins (HSPs) are molecular chaperones and have been implicated in longevity and aging in many organisms [ 47 ]. Meanwhile, the expression of hsp-4 and hsp-6 is a positive marker of unfolded protein response (UPR), which could respond to heat stress [ 48 , 49 ]. Aging worms show impaired activation of heat shock and UPRs [ 50 ].…”

The special unfolded protein response in plasma cells

“…Similarly, the anticipatory nature of UPR target induction is not unique to plasma cells. C elegans BiP is selectively induced by the developmental signals in specialized cells that produce cuticular structures known as alae, in anticipation of their differentiation from stem‐like into secretory cells 34 . Intriguingly, in that case, BiP induction is actively suppressed in sister cells that do not secrete alae by a transcriptional regulator BLMP‐1, whose mammalian homologue Blimp‐1 is a major regulator of ASC differentiation, and loss of this suppression results in defective cuticle production.…”

C. elegans Apical Extracellular Matrices Shape Epithelia

“…The high level of secretion presumably required to build a cuticle also relies on stress pathway regulation. Upregulation of ER stress proteins occurs in a developmentally regulated fashion during molting [ 165 ].…”