Rab7a modulates ER stress and ER morphology

Mateus, Duarte; Marini, Elettra Sara; Progida, Cinzia; Bakke, Oddmund

doi:10.1016/j.bbamcr.2018.02.011

Cited by 30 publications

(22 citation statements)

References 74 publications

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“…YIF1A recycles between the ER and the Golgi with a major ERGIC localization, maintaining homeostasis of the early secretory pathway (Yoshida et al, 2008). Rab7a modulates ER morphology by controlling ER stress responses (Mateus et al, 2018). Thus, these CoV-2 interactions may be crucial to controlling ER morphology and homeostasis, limiting induction of ER stress and apoptosis.…”

Section: Er Homeostasismentioning

confidence: 99%

Role of the early secretory pathway in SARS-CoV-2 infection

Sicari

Chatziioannou

Κουτσανδρέας

et al. 2020

Journal of Cell Biology

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Similar to other RNA viruses, SARS-CoV-2 must (1) enter a target/host cell, (2) reprogram it to ensure its replication, (3) exit the host cell, and (4) repeat this cycle for exponential growth. During the exit step, the virus hijacks the sophisticated machineries that host cells employ to correctly fold, assemble, and transport proteins along the exocytic pathway. Therefore, secretory pathway–mediated assemblage and excretion of infective particles represent appealing targets to reduce the efficacy of virus biogenesis, if not to block it completely. Here, we analyze and discuss the contribution of the molecular machines operating in the early secretory pathway in the biogenesis of SARS-CoV-2 and their relevance for potential antiviral targeting. The fact that these molecular machines are conserved throughout evolution, together with the redundancy and tissue specificity of their components, provides opportunities in the search for unique proteins essential for SARS-CoV-2 biology that could also be targeted with therapeutic objectives. Finally, we provide an overview of recent evidence implicating proteins of the early secretory pathway as potential antiviral targets with effective therapeutic applications.

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Section: Er Homeostasismentioning

confidence: 99%

Role of the early secretory pathway in SARS-CoV-2 infection

Sicari

Chatziioannou

Κουτσανδρέας

et al. 2020

Journal of Cell Biology

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“…Some of the apical vesicular structures containing ntChx were also positive for Rab7 (Figure 2c), a protein involved in early-to-late endosome maturation, modulation of ER homeostasis and stress, and endosome-to-TGN trafficking. [23][24][25] Similar to EEA1, Rab7/ntChx co-localizations were restricted to the apical region of enterocytes, with large Rab7 + vesicles being present that were consistent with lysosomal structure but which did not contain ntChx.…”

Section: In Vivo A→b Transcytosis Across Rat Intestinal Epitheliummentioning

confidence: 89%

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

et al. 2020

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Cholix (Chx) is expressed by the intestinal pathogen Vibrio cholerae as a single chain of 634 amino acids (~70.7 kDa protein) that folds into three distinct domains, with elements of the second and third domains being involved in accessing the cytoplasm of nonpolarized cells and inciting cell death via ADP-ribosylation of elongation factor 2, respectively. In order to reach nonpolarized cells within the intestinal lamina propria, however, Chx must cross the polarized epithelial barrier in an intact form. Here, we provide in vitro and in vivo demonstrations that a nontoxic Chx transports across intestinal epithelium via a vesicular trafficking pathway that rapidly achieves vesicular apical to basal (A→B) transcytosis and avoids routing to lysosomes. Specifically, Chx traffics in apical endocytic Rab7 + vesicles and in basal exocytic Rab11 + vesicles with a transition between these domains occurring in the ER-Golgi intermediate compartment (ERGIC) through interactions with the lectin mannose-binding protein 1 (LMAN1) protein that undergoes an intracellular redistribution that coincides with the reorganization of COPI + and COPII + vesicular structures. Truncation studies demonstrated that domain I of Chx alone was sufficient to efficiently complete A→B transcytosis and capable of ferrying genetically conjoined human growth hormone (hGH). These studies provide evidence for a pathophysiological strategy where native Chx exotoxin secreted in the intestinal lumen by nonpandemic V. cholerae can reach nonpolarized cells within the lamina propria in an intact form by using a nondestructive pathway to cross in the intestinal epithelial that appears useful for oral delivery of biopharmaceuticals. One-Sentence Summary: Elements within the first domain of the Cholix exotoxin protein are essential and sufficient for the apical to basal transcytosis of this Vibrio cholerae-derived virulence factor across polarized intestinal epithelial cells.

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“…A previous study showed that RAB7A gene expression in the postmortem brain was up-regulated in patients with depression who died by suicide [34]. Recently, RAB7A was demonstrated to modulate endoplasmic reticulum stress [35], which is associated with mood disorders [36,37]. Other functions of RAB7A include growth-factormediated cell signalling and lipid metabolism [38], which are also proposed mechanisms involved in the pathophysiology of mood disorders [39,40].…”

Section: Discussionmentioning

confidence: 99%

Comparison of serum protein profiles between major depressive disorder and bipolar disorder

et al. 2020

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Background: Major depressive disorder and bipolar disorder are prevalent and debilitating psychiatric disorders that are difficult to distinguish, as their diagnosis is based on behavioural observations and subjective symptoms. Quantitative protein profile analysis might help to objectively distinguish between these disorders and increase our understanding of their pathophysiology. Thus, this study was conducted to compare the peripheral protein profiles between the two disorders. Methods: Serum samples were collected from 18 subjects with major depressive disorder and 15 subjects with bipolar disorder. After depleting abundant proteins, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and label-free quantification were performed. Data-dependent acquisition data were statistically analysed from the samples of 15 subjects with major depressive disorder and 10 subjects with bipolar disorder who were psychotropic drug-free. Two-sided t-tests were performed for pairwise comparisons of proteomes to detect differentially-expressed proteins (DEPs). Ingenuity Pathway Analysis of canonical pathways, disease and functions, and protein networks based on these DEPs was further conducted. Results: Fourteen DEPs were significant between subjects with major depressive disorder and those with bipolar disorder. Ras-related protein Rab-7a (t = 5.975, p = 4.3 × 10 − 6) and Rho-associated protein kinase 2 (t = 4.782, p = 8.0 × 10 − 5) were significantly overexpressed in subjects with major depressive disorder and Exportin-7 (t =-4.520, p = 1.5 × 10 − 4) was significantly overexpressed in subjects with bipolar disorder after considering multiple comparisons. Bioinformatics analysis showed that cellular functions and inflammation/immune pathways were significantly different. Conclusions: Ras-related protein Rab-7a, Rho-associated protein kinase 2, and Exportin-7 were identified as potential peripheral protein candidates to distinguish major depressive disorder and bipolar disorder. Further large sample studies with longitudinal designs and validation processes are warranted.

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Rab7a modulates ER stress and ER morphology

Cited by 30 publications

References 74 publications

Role of the early secretory pathway in SARS-CoV-2 infection

Role of the early secretory pathway in SARS-CoV-2 infection

Cholix protein domain I functions as a carrier element for efficient apical to basal epithelial transcytosis

Comparison of serum protein profiles between major depressive disorder and bipolar disorder

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