A paralog-specific role of COPI vesicles in the neuronal differentiation of mouse pluripotent cells

Goyal, Manu; Zhao, Xiyan; Bozhinova, Mariya; Andrade-López, Karla; Heus, Cecilia de; Schulze-Dramac, Sandra; Müller-McNicoll, Michaela; Klumperman, Judith; Béthune, Julien

doi:10.26508/lsa.202000714

Cited by 11 publications

(5 citation statements)

References 69 publications

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“…Despite the described differences in localization of COPG1and COPG2-containing COPI vesicles within secretory pathway compartments 57 , the suggested functional difference between both paralogues has not yet been confirmed experimentally 58 . Proteomic profiling of γ1ζ1, γ1ζ2, γ2ζ1−COPI vesicle contents did not reveal significant differences 59 , however, mediation of specific transport directions has not been investigated.…”

Section: Hek293t Overexpressionmentioning

confidence: 92%

Deficiency in coatomer complex I causes aberrant activation of STING signalling

et al. 2022

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Coatomer complex I (COPI) mediates retrograde vesicular trafficking from Golgi to the endoplasmic reticulum (ER) and within Golgi compartments. Deficiency in subunit alpha causes COPA syndrome and is associated with type I IFN signalling, although the upstream innate immune sensor involved was unknown. Using in vitro models we find aberrant activation of the STING pathway due to deficient retrograde but probably not intra-Golgi transport. Further we find the upstream cytosolic DNA sensor cGAS as essentially required to drive type I IFN signalling. Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist. Finally, we demonstrate that inflammation in COPA syndrome patient peripheral blood mononuclear cells and COPI-deficient cell lines is ameliorated by treatment with the small molecule STING inhibitor H-151, suggesting targeted inhibition of the cGAS/STING pathway as a promising therapeutic approach.

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Section: Hek293t Overexpressionmentioning

confidence: 92%

Deficiency in coatomer complex I causes aberrant activation of STING signalling

et al. 2022

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“…ATF4-RL reporter was generated by PCR amplifying ATF4 5′UTR (ENSMUST00000109605.5) and cloning between SacI and NheI of RL. To generate GARS-myc-expressing plasmid, blasticidin resistance CDS was PCR amplified and cloned between SbfI and SanDI of piggyBac vector pCyl50-MCS (kind gift of Dr Julien Bethune ( 24 )), to generate piggyBac-Blast. GARS CDS (P41250-2) was PCR amplified from human cDNA and cloned between FseI and AgeI sites of piggyBac-Blast.…”

Section: Methodsmentioning

confidence: 99%

Charcot–Marie–Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response

Mendonsa

Kuegelgen

Bujanic

et al. 2021

Nucleic Acids Research

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Toxic gain-of-function mutations in aminoacyl-tRNA synthetases cause a degeneration of peripheral motor and sensory axons, known as Charcot–Marie–Tooth (CMT) disease. While these mutations do not disrupt overall aminoacylation activity, they interfere with translation via an unknown mechanism. Here, we dissect the mechanism of function of CMT mutant glycyl-tRNA synthetase (CMT-GARS), using high-resolution ribosome profiling and reporter assays. We find that CMT-GARS mutants deplete the pool of glycyl-tRNAGly available for translation and inhibit the first stage of elongation, the accommodation of glycyl-tRNA into the ribosomal A-site, which causes ribosomes to pause at glycine codons. Moreover, ribosome pausing activates a secondary repression mechanism at the level of translation initiation, by inducing the phosphorylation of the alpha subunit of eIF2 and the integrated stress response. Thus, CMT-GARS mutant triggers translational repression via two interconnected mechanisms, affecting both elongation and initiation of translation.

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“…The above results suggest that COPI disruption results in the inhibition of autophagy, which is involved in the mTORC1 pathway. In addition, the COPI vesicle possesses multiple functions, such as Golgi–ER trafficking [ 43 ], mitochondria–ER contact site formation [ 47 ], reactive oxygen production [ 48 ], and cell differentiation [ 49 ]. It has been reported that mitochondria–endoplasmic reticulum contact sites are involved in the formation of autophagosomes [ 50 ], which need further exploration.…”

Section: Discussionmentioning

confidence: 99%

COPI Vesicle Disruption Inhibits Mineralization via mTORC1-Mediated Autophagy

Nie,

Ma,

Zhang

et al. 2023

IJMS

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Bone mineralization is a sophisticated regulated process composed of crystalline calcium phosphate and collagen fibril. Autophagy, an evolutionarily conserved degradation system, whereby double-membrane vesicles deliver intracellular macromolecules and organelles to lysosomes for degradation, has recently been shown to play an essential role in mineralization. However, the formation of autophagosomes in mineralization remains to be determined. Here, we show that Coat Protein Complex I (COPI), responsible for Golgi-to-ER transport, plays a pivotal role in autophagosome formation in mineralization. COPI vesicles were increased after osteoinduction, and COPI vesicle disruption impaired osteogenesis. Mechanistically, COPI regulates autophagy activity via the mTOR complex 1 (mTORC1) pathway, a key regulator of autophagy. Inhibition of mTOR1 rescues the impaired osteogenesis by activating autophagy. Collectively, our study highlights the functional importance of COPI in mineralization and identifies COPI as a potential therapeutic target for treating bone-related diseases.

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A paralog-specific role of COPI vesicles in the neuronal differentiation of mouse pluripotent cells

Cited by 11 publications

References 69 publications

Deficiency in coatomer complex I causes aberrant activation of STING signalling

Deficiency in coatomer complex I causes aberrant activation of STING signalling

Charcot–Marie–Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response

COPI Vesicle Disruption Inhibits Mineralization via mTORC1-Mediated Autophagy

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