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The body's external surfaces and the insides of biological tubes, like the vascular system, are lined by a lipid-, glycoprotein-, and glycosaminoglycan-rich apical extracellular matrix (aECM). aECMs are the body's first line of defense against infectious agents and promote tissue integrity and morphogenesis, but are poorly described relative to basement membranes and stromal ECMs. While some aECM components, such as zona pellucida (ZP) domain proteins, have been identified, little is known regarding the overall composition of the aECM or the mechanisms by which different aECM components work together to shape epithelial tissues. In Caenorhabditis elegans, external epithelia develop in the context of an ill-defined ZP-containing aECM that precedes secretion of the collagenous cuticle. C. elegans has 43 genes that encode at least 65 unique ZP proteins, and we show that some of these comprise distinct precuticle aECMs in the embryo. Previously, the nidogen- and EGF-domain protein DEX-1 was shown to anchor dendrites to the C. elegans nose tip in concert with the ZP protein DYF-7. Here, we identified a new, strong loss-of-function allele of dex-1, cs201. dex-1 mutants die as L1 larvae and have a variety of tissue distortion phenotypes, including excretory defects, pharyngeal ingression, alae defects, and a short and fat body shape, that strongly resemble those of genes encoding ZP proteins. DEX-1 localizes to ZP-containing aECMs in the tissues that show defects in dex-1 mutants. Our studies suggest that DEX-1 is a component of multiple distinct embryonic aECMs that shape developing epithelia, and a potential partner of multiple ZP proteins. [ABSTRACT FROM AUTHOR]

Animals have evolved critical mechanisms to maintain cellular and organismal proteostasis during development, disease, and exposure to environmental stressors. The Unfolded Protein Response (UPR) is a conserved pathway that senses and responds to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen. We have previously demonstrated that the IRE-1-XBP-1 branch of the UPR is required to maintain Caenorhabditis elegans ER homeostasis during larval development in the presence of pathogenic Pseudomonas aeruginosa. In this study, we identify loss-of-function mutations in four conserved transcriptional regulators that suppress the larval lethality of xbp-1 mutant animals caused by immune activation in response to infection by pathogenic bacteria: FKH-9, a forkhead family transcription factor; ARID-1, an ARID/Bright domain-containing transcription factor; HCF-1, a transcriptional regulator that associates with histone modifying enzymes; and SIN-3, a subunit of a histone deacetylase complex. Further characterization of FKH-9 suggests that loss of FKH-9 enhances resistance to the ER toxin tunicamycin and results in enhanced ER-associated degradation (ERAD). Increased ERAD activity of fkh-9 loss-of-function mutants is accompanied by a diminished capacity to degrade cytosolic proteasomal substrates and a corresponding increased sensitivity to the proteasomal inhibitor bortezomib. Our data underscore how the balance between ER and cytosolic proteostasis can be influenced by compensatory activation of ERAD during the physiological ER stress of infection and immune activation. [ABSTRACT FROM AUTHOR]