Compartmentalization of Endoplasmic Reticulum Quality Control and ER-Associated Degradation Factors

Leitman, Julia; Ron, Efrat; Ogen‐Shtern, Navit; Lederkremer, Gerardo Z.

doi:10.1089/dna.2012.1889

Cited by 32 publications

(28 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This property, together with the enzymatic action of UDPGlc:glycoprotein glucosyltransferase and glucosidases I and II leads to a cyclic interaction of folding substrates with calnexin until proper folding is reached or ERAD is triggered. Our new data now indicate that calnexin itself undergoes a palmitoylationdependent cycle within the ER and shuttles back and forth from regulating Ca 2+ signaling at or close to the MAM and mediating protein folding and quality control at or close to the rough ER, including the targeting of unfolded or misfolded proteins to the ERQC (Leitman et al, 2013). Interestingly, these results could help explain the anti-stress function of 2-bromopalmitate (2BP) treatment, which attenuates the induction of ER stress transcription factors and the progression of apoptosis (Baldwin et al, 2012).…”

Section: Discussionmentioning

confidence: 83%

Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

Lynes

Raturi

Shenkman

et al. 2013

Journal of Cell Science

Self Cite

134

111

View full text Add to dashboard Cite

SummaryThe palmitoylation of calnexin serves to enrich calnexin on the mitochondria-associated membrane (MAM). Given a lack of information on the significance of this finding, we have investigated how this endoplasmic reticulum (ER)-internal sorting signal affects the functions of calnexin. Our results demonstrate that palmitoylated calnexin interacts with sarcoendoplasmic reticulum (SR) Ca 2+ transport ATPase (SERCA) 2b and that this interaction determines ER Ca 2+ content and the regulation of ER-mitochondria Ca 2+ crosstalk. In contrast, non-palmitoylated calnexin interacts with the oxidoreductase ERp57 and performs its well-known function in quality control. Interestingly, our results also show that calnexin palmitoylation is an ER-stress-dependent mechanism. Following a short-term ER stress, calnexin quickly becomes less palmitoylated, which shifts its function from the regulation of Ca 2+ signaling towards chaperoning and quality control of known substrates. These changes also correlate with a preferential distribution of calnexin to the MAM under resting conditions, or the rough ER and ER quality control compartment (ERQC) following ER stress. Our results have therefore identified the switch that assigns calnexin either to Ca 2+ signaling or to protein chaperoning.

show abstract

Section: Discussionmentioning

confidence: 83%

Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

Lynes

Raturi

Shenkman

et al. 2013

Journal of Cell Science

Self Cite

134

111

View full text Add to dashboard Cite

show abstract

“…Our data also suggest that these aggregates may reflect mutant s-1R clustering at ER subcompartments where BiP is excluded. One such specialization is the ER quality control compartment (ERQC), which forms during ER stress (Kamhi-Nesher et al, 2001;Frenkel et al, 2004;Kondratyev et al, 2007;Leitman et al, 2013). Indeed, pharmacologic induction of ER stress results in the clustering of the unfolded protein response proteins (UPR) protein kinase RNA-like ER kinase (Kondratyev et al, 2007) and inositol-requiring protein 1 (IRE1) at ERQCs (Kimata et al, 2007;Aragon et al, 2009;Li et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

et al. 2016

View full text Add to dashboard Cite

The sigma-1 receptor (s-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two s-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (D31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The s-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K 1 channel K ir 2.1, compared with the wild-type s-1R. Thus, these s-1R mutants have different functional properties that could contribute to their disease phenotypes.

show abstract

“…Several studies have reported on ER-derived inclusion-like structures that are formed after expression of mutated ER proteins in yeast or mammalian cells [55,58-60]. An ER-derived structure termed ERPO (ER protective organelle) has been identified as a protective ER compartment in cells expressing the serpin α1-antitrypsin with an E342K mutation, associated with liver disease in children [58].…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

Kuijpers

Dis

Haasdijk

et al. 2013

acta neuropathol commun

View full text Add to dashboard Cite

BackgroundProtein aggregation and the formation of intracellular inclusions are a central feature of many neurodegenerative disorders, but precise knowledge about their pathogenic role is lacking in most instances. Here we have characterized inclusions formed in transgenic mice carrying the P56S mutant form of VAPB that causes various motor neuron syndromes including ALS8.ResultsInclusions in motor neurons of VAPB-P56S transgenic mice are characterized by the presence of smooth ER-like tubular profiles, and are immunoreactive for factors that operate in the ER associated degradation (ERAD) pathway, including p97/VCP, Derlin-1, and the ER membrane chaperone BAP31. The presence of these inclusions does not correlate with signs of axonal and neuronal degeneration, and axotomy leads to their gradual disappearance, indicating that they represent reversible structures. Inhibition of the proteasome and knockdown of the ER membrane chaperone BAP31 increased the size of mutant VAPB inclusions in primary neuron cultures, while knockdown of TEB4, an ERAD ubiquitin-protein ligase, reduced their size. Mutant VAPB did not codistribute with mutant forms of seipin that are associated with an autosomal dominant motor neuron disease, and accumulate in a protective ER derived compartment termed ERPO (ER protective organelle) in neurons.ConclusionsThe data indicate that the VAPB-P56S inclusions represent a novel reversible ER quality control compartment that is formed when the amount of mutant VAPB exceeds the capacity of the ERAD pathway and that isolates misfolded and aggregated VAPB from the rest of the ER. The presence of this quality control compartment reveals an additional level of flexibility of neurons to cope with misfolded protein stress in the ER.

show abstract

Compartmentalization of Endoplasmic Reticulum Quality Control and ER-Associated Degradation Factors

Cited by 32 publications

References 67 publications

Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

Contact Info

Product

Resources

About