HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor

Abstract

Homocysteine-inducible, endoplasmic reticulum (ER) stress-inducible, ubiquitin-like domain member 1 (HERPUD1), an ER resident protein, is upregulated in response to ER stress and Ca2+ homeostasis deregulation. HERPUD1 exerts cytoprotective effects in various models, but its role during oxidative insult remains unknown. The aim of this study was to investigate whether HERPUD1 contributes to cytoprotection in response to redox stress and participates in mediating the stress-dependent signaling pathways. Our data showed that HERPUD1 protein levels increased in HeLa cells treated for 30 min with H2O2 or angiotensin II and in aortic tissue isolated from mice treated with angiotensin II for 3 weeks. Cell death was higher in HERPUD1 knockdown (sh-HERPUD1) in HeLa cells treated with H2O2 in comparison with control (sh-Luc) HeLa cells. This effect was abolished by the intracellular Ca2+ chelating agent BAPTA-AM or the inositol 1,4,5-trisphosphate receptor (ITPR) antagonist xestospongin B, suggesting that the response to H2O2 was dependent on intracellular Ca2+ stores and the ITPR. Ca2+ kinetics showed that sh-HERPUD1 HeLa cells exhibited greater and more sustained cytosolic and mitochondrial Ca2+ increases than sh-Luc HeLa cells. This higher sensitivity of sh-HERPUD1 HeLa cells to H2O2 was prevented with the mitochondrial permeability transition pore inhibitor cyclosporine A. We concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca2+ transfer from the ER to mitochondria.

Hematopoietic stem cells and lineage cells undergo dynamic alterations under microgravity and recovery conditions

“…High-throughput sequencing of HSCs provided insights into the molecular mechanism involved in the apoptosis of these cells. The results revealed the elevated expression of several molecular chaperones, including Hsph1, Hspa8, and Dnaja1, which encode heat shock proteins with antiapoptotic activities (26), as well as Herpud1, which is involved in protein processing in endoplasmic reticulum and protection against oxidative stress-induced apoptosis (27). Changes in the expression of all 4 proteins may have led to the increase in HSCs observed in the HU mice.…”

Herpud1 negatively regulates pathological cardiac hypertrophy by inducing IP3 receptor degradation

“…Cardiac hypertrophy is a pathological process favored by changes in Ca 2+ signaling. Cytoprotective proteins such as Herpud1 may regulate these signals, mainly by inducing degradation of ER proteins and maintaining Ca 2+ homeostasis 20 , 21 . To date, the presence of Herpud1 mRNA has only been reported in human cardiac tissue 17 .…”

“…Herpud1 has also been proposed as a regulator of Ca 2+ based on its capacity to modulate the release of this cation from the ER 20 , 21 . As mentioned, it remains unknown whether Herpud1 exercises this function in cardiomyocytes, where Ca 2+ signaling is crucial to a wide variety of intracellular processes including contraction, signal transduction, hypertrophy development, electrical signaling, gene transcription, and cell death 31 .…”

“…Herpud1 was subsequently reported to facilitate the retro-translocation of proteins from the ER to the 26 S proteasome in the cytosol for proteolytic elimination 18 – 20 . IP3R1 has been shown to be a Herpud1 target 20 with the ability to regulate intracellular Ca 2+ levels in neuron and HeLa cell lines 20 , 21 . This ability suggests a potential role in cardiac IP3R degradation, which occurs via the proteasome pathway 22 .…”

Ion Channels in Aging and Aging-Related Diseases

“…This nuclear Ca 2+ release is thought to control gene expression responsible for cellular survival and death pathways, and therefore, represents a promising drug target for neurodegenerative diseases [56]. This is exemplified by the recent finding that homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1) is cytoprotective by preventing IP 3 R-mediated Ca 2+ transfer from the ER to mitochondria [57]. Analogously to IP 3 Rs, several neurodegenerative and age-related disorders show RyR dysfunction contributing to disease pathology and progression.…”