The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Abstract

Cellular adaptation to environmental changes and stress relies on a wide range of regulatory mechanisms that are tightly controlled at several levels, including transcription. Chromatin structure and chromatin binding proteins are important factors contributing to the transcriptional response to stress. However, it remains largely unknown to what extent specific chromatin factors influence the response to distinct forms of stress in a developmental context. One of the best characterized stress response pathways is the unfolded protein response (UPR), which is activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). Here, we show that Caenorhabditis elegans heterochromatin protein like-2 (HPL-2), the homolog of heterochromatin protein 1 (HP1), downregulates the UPR in the intestine. Inactivation of HPL-2 results in an enhanced resistance to ER stress dependent on the X-box binding protein 1 (XBP-1)/inositol requiring enzyme 1 branch of the UPR and the closely related process of autophagy. Increased resistance to ER stress in animals lacking HPL-2 is associated with increased basal levels of XBP-1 activation and ER chaperone expression under physiological conditions, which may in turn activate an adaptive response known as ER hormesis. HPL-2 expression in intestinal cells is sufficient to rescue stress resistance, whereas expression in neuronal cells negatively influenced the ER stress response through a cell-nonautonomous mechanism. We further show that the retinoblastoma protein homolog LIN-35 and the LIN-13 zinc finger protein act in the same pathway as HPL-2 to limit the ER stress response. Altogether, our results point to multiple functions for HP1 in different cell types to maintain ER homeostasis.

Endoplasmic reticulum proteostasis impairment in aging

“…Importantly, other studies previously demonstrated that neuronal UPR regulates the innate immunity in the gut on a cell‐nonautonomous manner (Martinez & Hetz, ; Sun et al ., ; Aballay, ). Chromatin remodeling factors in neurons can also engage ER stress responses through a cell‐nonautonomous mechanism (Kozlowski et al ., ). Thus, accumulating evidence supports the idea that when an organism is exposed to environmental or pathogenic challenges, the ability of the nervous system to integrate these signals through the activation of the UPR favors the maintenance of homeostasis in various peripheral organs (Mardones et al ., ).…”

Lysosomes, Autophagy, and Hormesis in Cell Physiology, Pathology, and Age-Related Disease

“… 3 This type of functional response seems to occur in all eukaryotic organisms, which include yeasts and fungi, protozoans, plants, and metazoan animals. Lysosomal autophagy (self-eating) appears to be strongly associated with the mechanism underlying hormesis 4 - 8 ; and Blagosklonny 9 has proposed that the mechanistic target of rapamycin (mTOR) cell signaling system is a crucial feature of hormetic responses, particularly due to its relationship with lysosomal autophagy ( Figure 2 ).…”

A Forward Genetic Screen for Suppressors of Somatic P Granules inCaenorhabditis elegans

“…We generated a line with a fosmid containing lin-13 (marked with a myo-3 ::mCherry transgene) ( Figure 4B ) and observed rescue in 14 of 20 L4-staged worms carrying the transgene; 28/28 siblings without the transgene re-expressed intestinal PGL-1::GFP, suggesting that the amino acid substitution in LIN-13 is responsible for the phenotype. LIN-13 is a known lin-35 /Rb pathway component that binds and recruits the heterochromatin protein HPL-2 to distinct nuclear foci ( Meléndez and Greenwald 2000 ; Coustham et al 2006 ) and also acts with LIN-35 and HPL-2 to dampen the ER stress response ( Kozlowski et al 2014 ). In addition to being a known synMuv B gene, lin-13 mutants were previously shown to exhibit somatic P-granule expression ( Wang et al 2005 ), suggesting that sam4 could be a hypomorphic allele of lin-13 that is not strong enough to cause a synMuv phenotype when combined with lin-15a RNAi.…”