Biosynthesis of inositol trisphosphate receptors: selective association with the molecular chaperone calnexin

Joseph, Suresh K.; Boehning, Darren; Bokkala, Shaila; Watkins, Richard H.; Widjaja, Johan

doi:10.1042/bj3420153

Cited by 21 publications

(10 citation statements)

References 49 publications

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“…Conformational maturation of the newly synthesized tetramer is probably a complex process that involves interaction with ER chaperones. An alternative possibility is that failure to acquire the proper conformation contributes to the decreased stability of the newly synthesized InsP 3 R. A transient association of newly synthesized InsP 3 Rs with calnexin (but not calreticulin) has been observed previously [33].…”

Section: Discussionmentioning

confidence: 70%

Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells

Khan

Joseph

2003

Biochemical Journal

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A comparison of the basal degradation of type I Ins P3Rs [L- myo -inositol 1,4,5-trisphosphate receptor], measured by pulse-chase analysis or by analysis of immunoreactive Ins P3Rs after cycloheximide addition, indicated that the small pool of newly synthesized radioactive Ins P3Rs degraded relatively rapidly compared with the large pool of mature Ins P3Rs. An antibody (Ab) against a peptide sequence within the IL-3 (third intraluminal loop) of the receptor (IL-3 Ab) was used to identify protected proteolytic fragments that may accumulate in cells. The IL-3 Ab recognized a 56 kDa fragment in both WB rat liver cells and A7R5 smooth-muscle cells. Gel filtration experiments indicated that the 56 kDa fragment was monomeric and, based on reactivity to other Abs, was missing the cytosol-exposed N- and C-terminal segments of the receptor. The addition of the lysosomal protease inhibitor chloroquine resulted in the rapid disappearance of the 56 kDa band. This effect was mimicked by the cysteine protease inhibitors leupeptin, N -acetyl-L-leucyl-L-leucyl-L-methioninal and N -acetyl-leucyl-leucyl-norleucinal. Lactacystin and NH4Cl were less effective. A second fragment of 16 kDa containing the C-terminus accumulated only when the cells were treated with NH4Cl, and not with any of the other inhibitors tested. No N-terminal-reactive fragments were observed. We propose that mature Ins P3R tetramers dissociate into monomers and that the 56 kDa fragment is a cleavage intermediate of the monomer representing the six transmembrane domains. Angiotensin-II-stimulated down-regulation of Ins P3Rs in WB cells has been shown to involve the ubiquitin/proteasome pathway. Angiotensin-II treatment of WB cells neither resulted in the accumulation of any new fragments nor increased the levels of the 56 or 16 kDa fragments. We conclude that basal and agonist-stimulated degradations of Ins P3Rs occur by different pathways. The agonist-mediated pathway involves the concerted removal and proteolysis of the entire receptor molecule from the endoplasmic reticulum membrane without the appearance of intermediate intraluminal fragments.

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Section: Discussionmentioning

confidence: 70%

Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells

Khan

Joseph

2003

Biochemical Journal

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“…First, GRP78 knockdown did not cause misfolding-dependent retrodegradation or aggregation of IP 3 R1. Second, GRP78 knockdown did not affect N-linked glycosylation, supporting that IP 3 R1 is normally folded by the ER lectin chaperone calnexin (Joseph et al, 1999;Ellgaard and Helenius, 2003) and that IP 3 R1 does not undergo disassembly-dependent degradation (Khan and Joseph, 2003). Third, the specific binding behavior of GRP78 to IP 3 R1 is incompatible with typical binding behaviors of GRP78 to unfolded substrates regarding the dissociation kinetics and the preferences of ATP and ADP (Misselwitz et al, 1998;Hendershot, 2004;Nawa et al, 2007).…”

Section: Discussionmentioning

confidence: 94%

Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor

Higo

Hamada

Hisatsune

et al. 2010

Neuron

139

106

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Deranged Ca(2+) signaling and an accumulation of aberrant proteins cause endoplasmic reticulum (ER) stress, which is a hallmark of cell death implicated in many neurodegenerative diseases. However, the underlying mechanisms are elusive. Here, we report that dysfunction of an ER-resident Ca(2+) channel, inositol 1,4,5-trisphosphate receptor (IP(3)R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP(3)R (IP(3)R1) resulted in neuronal vulnerability to ER stress in vivo, and IP(3)R1 knockdown enhanced ER stress-induced apoptosis via mitochondria in cultured cells. The IP(3)R1 tetrameric assembly was positively regulated by the ER chaperone GRP78 in an energy-dependent manner. ER stress induced IP(3)R1 dysfunction through an impaired IP(3)R1-GRP78 interaction, which has also been observed in the brain of Huntington's disease model mice. These results suggest that IP(3)R1 senses ER stress through GRP78 to alter the Ca(2+) signal to promote neuronal cell death implicated in neurodegenerative diseases.

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“…Sig-1R Chaperone Attenuates IP3R3 Degradation IP3Rs degrade through multiple pathways. Newly synthesized IP3Rs, whose folding processes involve a transient association with calnexin, degrade rapidly (Joseph et al, 1999). Channel-forming tetramers of mature IP3Rs have considerably long half-lives.…”

Section: Sig-1rs Stabilize Ip3r3s At Mammentioning

confidence: 99%

Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival

Hayashi

2007

Cell

1,543

1,918

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Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.

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Biosynthesis of inositol trisphosphate receptors: selective association with the molecular chaperone calnexin

Cited by 21 publications

References 49 publications

Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells

Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells

Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor

Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell Survival

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