ER storage diseases: a role for ERGIC-53 in controlling the formation and shape of Russell bodies

Mattioli, Laura; Anelli, Tiziana; Fagioli, Claudio; Tacchetti, Carlo; Sitia, Roberto; Valetti, Caterina

doi:10.1242/jcs.02977

Cited by 58 publications

(88 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…82 However, Russell bodies were not detectable in pre-Golgi intermediates as was also reported for cells expressing aberrant Ig light chains. 50,76,77 The presence of various types of misfolded glycoproteins in the preGolgi intermediates [47][48][49][50]83 is in agreement with its function as a protein quality control checkpoint. 84 -87 Altogether, the present results show that aggregates formed by WT and mutant MYOC result in Russell body formation, a structural hallmark of ER storage diseases.…”

Section: Discussionmentioning

confidence: 66%

“…74,75 On the other hand, misfolded secretory proteins may form insoluble aggregates in the lumen of the ER, so-called Russell bodies. 45,50,76,77 In the classic meaning, Russell bodies are dilated rough ER cisternae containing aggregated, secretion-incompetent immunoglobulins that can neither be retrotranslocated nor be degraded by the ubiquitin-proteasome system. However, Russell bodies can be caused by other types of misfolded proteins and in nonlymphoid cell types.…”

Section: Discussionmentioning

confidence: 99%

“…Misfolded proteins have been detected in pre-Golgi intermediates and may cause its expansion. [47][48][49][50] We also detected mutant and WT MYOC in the pre-Golgi intermediates by confocal double immunofluorescence using the anti-ERGIC-53 antibody 51 as a marker for this structure (Figure 3, F and G). Although Russell bodies were detectable in the cytoplasm, none were observed in the ERGIC-53-positive elements ( Figure 3E), which is in agreement with the ultrastructural findings ( Figure 3C).…”

Section: Heteromeric Complexes Of Wt and Mutant Myoc Form Rough Er-dementioning

confidence: 91%

See 2 more Smart Citations

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Yam

Gaplovská-Kyselá

Zuber

et al. 2007

The American Journal of Pathology

124

View full text Add to dashboard Cite

Primary open-angle glaucoma with elevated intraocular pressure is a leading cause of blindness worldwide. Mutations of myocilin are known to play a critical role in the manifestation of the disease. Misfolded mutant myocilin forms secretion-incompetent intracellular aggregates. The block of myocilin secretion was proposed to alter the extracellular matrix environment of the trabecular meshwork, with subsequent impediment of aqueous humor outflow leading to elevated intraocular pressure. However, the molecular pathogenesis of myocilin-caused glaucoma is poorly defined. In this study, we show that heteromeric complexes composed of wild-type and mutant myocilin were retained in the rough endoplasmic reticulum, aggregating to form inclusion bodies typical of Russell bodies. The presence of myocilin aggregates induced the unfolded protein response proteins BiP and phosphorylated endoplasmic reticulum-localized eukaryotic initiation factor-2␣ kinase (PERK) with the subsequent activation of caspases 12 and 3 and expression of C/EBP homologous protein (CHOP)/GADD153, leading to apoptosis. Our findings identify endoplasmic reticulum stress-induced apoptosis as a pathway to explain the reduction of trabecular meshwork cells in patients with myocilincaused glaucoma. As a consequence, the phagocytotic capacity of the remaining trabecular meshwork cell population would be insufficient for effective cleaning of aqueous humor, constituting a major pathogenetic factor for the development of Glaucoma is a heterogeneous group of optic neuropathies characterized by a progressive degeneration of the optic nerve resulting in an irreversible loss of vision. 1After age-related macular degeneration, it is the second leading cause of severe vision loss or blindness.2 It is expected that ϳ4% of the world population older than the age of 40 will develop glaucoma. Primary open-angle glaucoma (POAG) is the most common form of the disease.2 In most cases of POAG, the aqueous humor outflow from the anterior eye chamber is impeded, resulting in an elevated intraocular pressure (IOP) and causing ganglion cell death in the neural retina.3,4 Hence, impaired outflow drainage along the trabecular meshwork (TM) and Schlemm's canal seems to be central in the pathogenesis of POAG. 3,4

show abstract

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Heteromeric Complexes Of Wt and Mutant Myoc Form Rough Er-dementioning

confidence: 91%

See 1 more Smart Citation

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Yam

Gaplovská-Kyselá

Zuber

et al. 2007

The American Journal of Pathology

124

View full text Add to dashboard Cite

show abstract

“…In addition to FV and FVIII, other potential LMAN1 cargo proteins have been identified. [26][27][28][29][30][31] Some of these cargo proteins, such as CatC and CatZ, do not seem to require MCFD2. 24 Thus, MCFD2 may be a specific cargo selection protein for the recruitment of FV and FVIII, but not other cargo proteins, such as CatC and CatZ.…”

Section: Discussionmentioning

confidence: 99%

EF-hand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII

Zheng

Liu

Zhou

et al. 2010

Blood

View full text Add to dashboard Cite

Combined deficiency of factor V and factor VIII (F5F8D) is a bleeding disorder caused by mutations in either LMAN1 or MCFD2. LMAN1 (ERGIC-53) and MCFD2 form a Ca 2؉ -dependent cargo receptor that cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment for efficient transport of FV/FVIII from the ER to the Golgi. Here we show that the C-terminal EF-hand domains are both necessary and sufficient for MCFD2 to interact with LMAN1. MCFD2 with a deletion of the entire N-terminal non-EF hand region still retains the LMAN1-binding function. Deletions that disrupt core structure of the EF-hand domains abolish LMAN1 binding. Circular dichroism spectroscopy studies on missense mutations localized to different structural elements of the EF-hand domains suggest that Ca 2؉ -induced folding is important for LMAN1 interaction. The EF-hand domains also mediate the interaction with FV and FVIII. However, mutations in MCFD2 that disrupt the tertiary structure and abolish LMAN1 binding still retain the FV/FVIII binding activities, suggesting that this interaction is independent of Ca 2؉ -induced folding of the protein. Our results suggest that the EF-hand domains of MCFD2 contain separate binding sites for LMAN1 and FV/FVIII that are essential for cargo receptor formation and cargo loading in the ER. (Blood.

show abstract

“…CPA was then removed allowing restoration of [Ca 2+ ] ER (reviewed in ref. 24 and Andrea Orsi and Roberto Sitia, unpublished results). In the absence of SERCA inhibitors, PrP glycosylation returned to the basal levels ( Fig.…”

mentioning

confidence: 70%

Interplays Between Covalent Modifications in the Endoplasmic Reticulum Increase Conformational Diversity in Nascent Prion Protein

Orsi

Sitia

2007

Prion

View full text Add to dashboard Cite

Previously published online as a Prion E-publication http://www.landesbioscience.com/journals/prion/article/5727 Key wORdSCa 2+ homeostasis, ER-golgi transport, GPIanchoring, N-glycosylation, oxidative folding, redox regulation AbStRActPrion protein (PrP), the causative agent of transmissible spongiform encephalopathies, is synthesized in the endoplasmic reticulum (ER) where it undergoes numerous covalent modifications. Here we investigate the interdependence and regulation of PrP oxidative folding, N-glycosylation and GPI addition in diverse ER conditions. Our results show that formation of the single disulphide bond is a pivotal event, essential for PrP transport, and can occur post-translationally. Retarding its formation enhances N-glycosylation and GPI-anchoring. In contrast, lowering ER Ca 2+ concentration inhibits N-glycosylation and GPI-anchoring. These data reveal tight interplays between the different ER covalent modifications, which collectively increase of PrP conformational diversity and may be important for its propagation.

show abstract

ER storage diseases: a role for ERGIC-53 in controlling the formation and shape of Russell bodies

Cited by 58 publications

References 52 publications

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

EF-hand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII

Interplays Between Covalent Modifications in the Endoplasmic Reticulum Increase Conformational Diversity in Nascent Prion Protein

Contact Info

Product

Resources

About