Adapting Secretory Proteostasis and Function Through the Unfolded Protein Response

Abstract

Cells address challenges to protein folding in the secretory pathway by engaging endoplasmic reticulum (ER)-localized protective mechanisms that are collectively termed the unfolded protein response (UPR). By the action of the transmembrane signal transducers IRE1, PERK, and ATF6, the UPR induces networks of genes whose products alleviate the burden of protein misfolding. The UPR also plays instructive roles in cell differentiation and development, aids in the response to pathogens, and coordinates the output of professional secretory cells. These functions add to and move beyond the UPR’s classical role in addressing proteotoxic stress. Thus, the UPR is not just a reaction to protein misfolding, but also a fundamental driving force in physiology and pathology. Recent efforts have yielded a suite of chemical genetic methods and small molecule modulators that now provide researchers with both stress-dependent and -independent control of UPR activity. Such tools provide new opportunities to perturb the UPR and thereby study mechanisms for maintaining proteostasis in the secretory pathway. Numerous observations now hint at the therapeutic potential of UPR modulation for diseases related to the misfolding and/or aggregation of ER client proteins. Growing evidence also indicates the promise of targeting ER proteostasis nodes downstream of the UPR. Here, we review selected advances in these areas, providing a resource to inform ongoing studies of secretory proteostasis and function as they relate to the UPR.

XBP1s activation can globally remodel N-glycan structure distribution patterns

“…Moreover, because the sugars on cell-surface proteins or on proteins secreted from an XBP1s-activated cell can be molecularly distinct from those of an unactivated cell, these findings reveal a potential new mechanism for translating intracellular stress signaling into altered interactions with the extracellular environment. T he unfolded protein response (UPR) is classically responsible for maintaining proteostasis in the secretory pathway (1). In the metazoan UPR, three transmembrane proteins (IRE1, PERK, and ATF6) act to detect protein misfolding stress in the endoplasmic reticulum (ER).…”

“…Moreover, chronic up-regulation of the XBP1s transcription factor is a pathologic hallmark of numerous malignancies (11). Consistent with its diverse regulatory functions, the IRE1-XBP1s arm can be activated independent of PERK-ATF4 and ATF6 in response to assorted stimuli (1). Attaining mechanistic understanding of these diverse processes requires first comprehensively defining the molecular consequences of XBP1s induction.…”

A new role for HERPUD1 and ERAD activation in osteoblast differentiation and mineralization

“…Many factors, including ER chaperone content, ER calcium concentration, foldase activity, and efficient protein quality control, are crucial at this step. Proteins that have achieved proper conformation continue through the secretory pathway, whereas misfolded and unfolded proteins are retained in the ER and degraded by ERAD or autophagy (9). Any imbalance in ER homeostasis triggers ER stress.…”

“…Transitioning from preosteoblast to mature osteoblast requires the activation of a genetic program that is commanded by the master transcriptional factors, runt-related transcription factor 2 (RUNX2) (7) and osterix (OSX) (8). Secretory cells, such as osteoblasts, require a finely tuned control to maintain proteostasis, including the regulation of protein biogenesis, folding, assembly, trafficking, and degradation (9).…”

Regulation of growth hormone biosynthesis by Cdk5 regulatory subunit associated protein 1-like 1 (CDKAL1) in pituitary adenomas

“…We finally investigated the molecular mechanism underlying the differential regulation of CDKAL1 activity in GHPAs and NFPAs. In general, synthesis of large amounts of secretory proteins inevitably leads to production of aberrant proteins, which causes proteostatic stress in secretory cells [24]. In contrast with NFPAs, the majority of protein synthesis in GHPAs is dedicated to biosynthesis of GH [15].…”