A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress

Li, Xia; Sun, Sha; Appathurai, Suhila; Sundaram, Arunkumar; Plumb, Rachel; Mariappan, Malaiyalam

doi:10.1016/j.celrep.2020.108563

Cited by 35 publications

(39 citation statements)

References 63 publications

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“…We were surprised to observe a total lack of detectable cluster formation upon induction of ER stress ( Fig. 1E ), in direct contrast to previous work by us and others that relied on ectopic expression of GFP-tagged IRE1 protein ( 20 , 21 , 28 – 32 ). While unexpected, this observation does not rule out lower-order IRE1 oligomerization at endogenous expression levels, since the limited sensitivity of confocal microscopy would preclude the detection of small oligomers such as dimers or tetramers as distinct morphological features.…”

Section: Resultscontrasting

confidence: 99%

Endoplasmic reticulum stress activates human IRE1α through reversible assembly of inactive dimers into small oligomers

Belyy

Zuazo-Gaztelu²,

Alamban

et al. 2021

Preprint

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Protein folding homeostasis in the endoplasmic reticulum (ER) is regulated by a signaling network, termed the unfolded protein response (UPR). Inositol-requiring enzyme 1 (IRE1) is an ER membrane-resident kinase/RNase that mediates signal transmission in the most evolutionarily conserved branch of the UPR. Dimerization and/or higher-order oligomerization of IRE1 are thought to be important for its activation mechanism, yet the actual oligomeric states of inactive, active, and attenuated mammalian IRE1 complexes remained unknown. We developed an automated two-color single-molecule tracking approach to dissect the oligomerization of tagged endogenous human IRE1 in live cells. In contrast to previous models, our data indicate that IRE1 exists as a constitutive homodimer at baseline and assembles into small oligomers upon ER stress. We demonstrate that the formation of inactive dimers and stress-dependent oligomers is fully governed by IRE1's lumenal domain. Phosphorylation of IRE1's kinase domain occurs more slowly than oligomerization and is retained after oligomers disassemble back into dimers. Our findings suggest that assembly of IRE1 dimers into larger oligomers specifically enables trans-autophosphorylation, which in turn drives IRE1's RNase activity.

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Section: Resultscontrasting

confidence: 99%

Endoplasmic reticulum stress activates human IRE1α through reversible assembly of inactive dimers into small oligomers

Belyy

Zuazo-Gaztelu²,

Alamban

et al. 2021

Preprint

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“…If BiP is indeed the principal regulator of UPR activation, then the removal of BiP binding sites from IRE1α should lead to an uncontrolled, chronic activation of the UPR. An engineered, 'BiP-less' variant of IRE1α that barely co-immunoprecipitates with BiP, however, is still responsive to ER stress-inducing agents and causes prolonged durations of UPR signaling [103]. Analogous experiments and observations have also been made in S. cerevisiae [104,105].…”

Section: A Closer Look On Indirect Models Of Sensing -Co-opting Bip As a Sensormentioning

confidence: 81%

“…A picture emerges in which IRE1α/ScIRE1 forms complex interactions with the entire machinery involved in the production, translocation, and folding of proteins at the entry point of the secretory pathway [67]. The intricate connection between IRE1α, the ribosome [67,118], and the Sec61/Sec63 translocon [77,103,119], together with IRE1α's ability to degrade mRNAs via RIDD [66], provide all ingredients for a selective degradation of mRNAs encoding for those proteins, which are particularly problematic to fold such as multidomain membrane proteins. The recent observation from in situ cryo-electron microscopy that signaling-active clusters of IRE1α remodel the ER membrane with the MHC-like binding groove pointing towards the surface of the ER membrane puts a spotlight on the role of the ER membrane in controlling UPR activity [120].…”

Section: A Closer Look On the Direct Model -Unfolded Proteins As Agonistsmentioning

confidence: 99%

“…Different membrane environments have likely provided different evolutionary constraints leading into different strategies of sensing LBS. Dissecting the role of IRE1α's amphipathic helix in LBS will be challenging because this region of IRE1α is also involved in an interaction with the Sec61/Sec63 translocon [103,200]. Because protein translocation can also be blocked by an aberrant membrane stiffening [177,188], it will be interesting to learn if the UPR coordinates membrane protein insertion and folding with a physicochemical ER membrane homeostasis by balancing the rate of protein and lipid production.…”

Section: Xhow Upr Transducers Sense Membrane Stiffening From Lipid Bilayer Stressmentioning

confidence: 99%

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The Unfolded Protein Response as Guardian of the Secretory Pathway

Radanović¹,

Ernst²

2021

Preprint

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The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10.000 different secretory and membrane proteins. The membrane insertion of proteins, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid metabolism for membrane lipids including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein folding-imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

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“…A picture emerges in which IRE1α/ScIRE1 forms complex interactions with the entire machinery involved in the production, translocation, and folding of proteins at the entry point of the secretory pathway [ 67 ]. The intricate connection between IRE1α, the ribosome [ 67 , 118 ], and the Sec61/Sec63 translocon [ 77 , 103 , 119 ], together with IRE1α’s ability to degrade mRNAs via RIDD [ 66 ], provides all ingredients for a selective degradation of mRNAs encoding for those proteins, which are particularly problematic to fold such as multidomain membrane proteins. The recent observation from in situ cryo-electron microscopy, that signaling-active clusters of IRE1α remodel the ER membrane with the MHC-like binding groove pointing towards the surface of the ER membrane, puts a spotlight on the role of the ER membrane in controlling UPR activity [ 120 ].…”

Section: A Closer Look On the Direct Model—unfolded Proteins As Agonistsmentioning

confidence: 99%

The Unfolded Protein Response as a Guardian of the Secretory Pathway

Radanović

Ernst

2021

Cells

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

show abstract

A Molecular Mechanism for Turning Off IRE1α Signaling during Endoplasmic Reticulum Stress

Cited by 35 publications

References 63 publications

Endoplasmic reticulum stress activates human IRE1α through reversible assembly of inactive dimers into small oligomers

Endoplasmic reticulum stress activates human IRE1α through reversible assembly of inactive dimers into small oligomers

The Unfolded Protein Response as Guardian of the Secretory Pathway

The Unfolded Protein Response as a Guardian of the Secretory Pathway

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