scholarly journals Atlastin-mediated membrane tethering is critical for cargo mobility and exit from the endoplasmic reticulum

2019 ◽  
Vol 116 (28) ◽  
pp. 14029-14038 ◽  
Author(s):  
Liling Niu ◽  
Tianji Ma ◽  
Feng Yang ◽  
Bing Yan ◽  
Xiao Tang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Critical Role ◽  
Spastic Paraplegia ◽  
Exit Site ◽  
Cargo Proteins ◽  
Membrane Tethering ◽  
Copii Vesicles ◽  
Er Export ◽  
In Cells

Endoplasmic reticulum (ER) membrane junctions are formed by the dynamin-like GTPase atlastin (ATL). Deletion of ATL results in long unbranched ER tubules in cells, and mutation of human ATL1 is linked to hereditary spastic paraplegia. Here, we demonstrate that COPII formation is drastically decreased in the periphery of ATL-deleted cells. ER export of cargo proteins becomes defective; ER exit site initiation is not affected, but many of the sites fail to recruit COPII subunits. The efficiency of cargo packaging into COPII vesicles is significantly reduced in cells lacking ATLs, or when the ER is transiently fragmented. Cargo is less mobile in the ER in the absence of ATL, but the cargo mobility and COPII formation can be restored by ATL R77A, which is capable of tethering, but not fusing, ER tubules. These findings suggest that the generation of ER junctions by ATL plays a critical role in maintaining the necessary mobility of ER contents to allow efficient packaging of cargo proteins into COPII vesicles.

scholarly journals The Rod-Shaped ATG2A-WIPI4 Complex Tethers Membranes In Vitro

Contact ◽  
2018 ◽  
Vol 1 ◽  
pp. 251525641881993 ◽  
Author(s):  
Takanori Otomo ◽  
Saikat Chowdhury ◽  
Gabriel C. Lander
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Critical Step ◽  
Molecular Events ◽  
Biochemical Studies ◽  
Membrane Tethering ◽  
Cytoplasmic Content ◽  
Autophagy Pathway ◽  
Copii Vesicles

The autophagosome precursor membrane, termed the isolation membrane or phagophore, emerges adjacent to a phosphatidylinositol 3-phosphate (PI3P)-enriched transient subdomain of the endoplasmic reticulum called the omegasome, thereafter expanding to engulf cytoplasmic content. Uncovering the molecular events that occur in the vicinity of the omegasome during phagophore biogenesis is imperative for understanding the mechanisms involved in this critical step of the autophagy pathway. We recently characterized the ATG2A-WIPI4 complex, one of the factors that localize to the omegasome and play a critical role in mediating phagophore expansion. Our structural and biochemical studies revealed that ATG2A is a rod-shaped protein with membrane-interacting properties at each end, endowing ATG2A with membrane-tethering capability. Association of the PI3P-binding protein WIPI4 at one of the ATG2A tips enables the ATG2A-WIPI4 complex to specifically tether PI3P-containing membranes to non-PI3P-containing membranes. We proposed models for the ATG2A-WIPI4 complex-mediated membrane associations between the omegasome and surrounding membranes, including the phagophore edge, the endoplasmic reticulum, ATG9 vesicles, and COPII vesicles.

Localization and quantification of endoplasmic reticulum Ca(2+)-ATPase isoform transcripts

1995 ◽  
Vol 269 (3) ◽  
pp. C775-C784 ◽  
Author(s):  
K. D. Wu ◽  
W. S. Lee ◽  
J. Wey ◽  
D. Bungard ◽  
J. Lytton
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Qualitative Assessment ◽  
Cell Physiology ◽  
Striated Muscles ◽  
Physiological Processes ◽  
Alternatively Spliced ◽  
Spleen Lymphocytes ◽  
Fast Twitch ◽  
In Cells

The Ca(2+)-adenosinetriphosphatase pump of the sarcoplasmic or endoplasmic reticulum (SERCA) plays a critical role in Ca2+ signaling and homeostasis in all cells and is encoded by a family of homologous and alternatively spliced genes. To understand more clearly the role the different isoforms play in cell physiology, we have undertaken a quantitative and qualitative assessment of the tissue distribution of transcripts encoding each SERCA isoform. SERCA1 expression is restricted to fast-twitch striated muscles, SERCA2a to cardiac and slow-twitch striated muscles, whereas SERCA2b is ubiquitously expressed. SERCA3 is expressed most abundantly in large and small intestine, thymus, and cerebellum and at lower levels in spleen, lymph node, and lung. In situ hybridization analyses revealed SERCA3 transcripts in cells of the intestinal crypt, the thymic cortex, and Purkinje cells in cerebellum. In addition, SERCA3 was expressed abundantly in isolated rat spleen lymphocytes, in various murine lymphoid cell lines, and in primary cultured microvascular endothelial cells. This analysis demonstrates that SERCA3 is expressed selectively in cells in which Ca2+ signaling plays a critical and sensitive role in regulating physiological processes.

scholarly journals ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Wenfu Ma ◽  
Elena Goldberg ◽  
Jonathan Goldberg
Keyword(s):  
Endoplasmic Reticulum ◽  
Retrieval System ◽  
Protein Sorting ◽  
Ldl Receptor ◽  
Retention Mechanism ◽  
Protein Uptake ◽  
Er Retention ◽  
Cargo Proteins ◽  
P24 Protein ◽  
Copii Vesicles

Native cargo proteins exit the endoplasmic reticulum (ER) in COPII-coated vesicles, whereas resident and misfolded proteins are substantially excluded from vesicles by a retention mechanism that remains unresolved. We probed the ER retention process using the proteostasis regulator 4-phenylbutyrate (4-PBA), which we show targets COPII protein to reduce the stringency of retention. 4-PBA competes with p24 proteins to bind COPII. When p24 protein uptake is blocked, COPII vesicles package resident proteins and an ER-trapped mutant LDL receptor. We further show that 4-PBA triggers the secretion of a KDEL-tagged luminal resident, implying that a compromised retention mechanism causes saturation of the KDEL retrieval system. The results indicate that stringent ER retention requires the COPII coat machinery to actively sort biosynthetic cargo from diffusible misfolded and resident ER proteins.

scholarly journals Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Belgin Yalçın ◽  
Lu Zhao ◽  
Martin Stofanko ◽  
Niamh C O'Sullivan ◽  
Zi Han Kang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Membrane Curvature ◽  
Degenerative Disease ◽  
Ultrastructural Analysis ◽  
Motor Axons ◽  
Spastic Paraplegia ◽  
Partial Loss ◽  
And Function ◽  
Tubular Endoplasmic Reticulum

Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

scholarly journals Hereditary spastic paraplegia associated with a rare endoplasmic reticulum lipid raft-associated protein 2 mutation

2020 ◽  
Vol 7 (10) ◽  
pp. 2077
Author(s):  
Sai Chandar Dudipala ◽  
Naveen Reddy Cheruku ◽  
Krishna Chaithanya Battu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cerebral Palsy ◽  
Lipid Raft ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Recessive ◽  
Adult Population ◽  
Complex Form ◽  
Spastic Paraplegia ◽  
Childhood Onset ◽  
Exonic Deletion

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. It can present as pure form or complex form. It can be present from infancy to adulthood, but majority in adult population. Childhood onset HSP must be differentiated from common conditions like cerebral palsy, neurodegenerative disorders and metabolic disorders. Many patients with pediatric HSP are mistakenly diagnosed with cerebral palsy. In children with spastic paraplegia in whom no acquired cause identified, HSP should be considered. Here we diagnosed a 6-year-old boy with HSP who presented with progressive spastic paraplegia, intellectual disability, seizures, joint contractures and cataract. His genetic study revealed exonic deletion of endoplasmic reticulum lipid raft-associated protein gene, which is associated with complicated Autosomal recessive HSP 18 (SPG18). HSP 18 was rarely described in literature.

scholarly journals Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matias Wagner ◽  
Daniel P. S. Osborn ◽  
Ina Gehweiler ◽  
Maike Nagel ◽  
Ulrike Ulmer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Degradation Pathway ◽  
Therapeutic Interventions ◽  
Spastic Paraplegia ◽  
Ubiquitin E3 Ligase ◽  
Wide Range ◽  
Inositol 1,4,5 Trisphosphate ◽  
Cerebellar Ataxias ◽  
Trisphosphate Receptor

Abstract Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

Spastin, the most commonly mutated protein in hereditary spastic paraplegia interacts with Reticulon 1 an endoplasmic reticulum protein

Neurogenetics ◽  
2006 ◽  
Vol 7 (2) ◽  
pp. 93-103 ◽  
Author(s):  
Ashraf U. Mannan ◽  
Johann Boehm ◽  
Simone M. Sauter ◽  
Anne Rauber ◽  
Paula C. Byrne ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Endoplasmic Reticulum Protein

Decreased expression of the mitochondrial matrix proteases Lon and ClpP in cells from a patient with hereditary spastic paraplegia (SPG13)

Neuroscience ◽  
2008 ◽  
Vol 153 (2) ◽  
pp. 474-482 ◽  
Author(s):  
J. Hansen ◽  
T.J. Corydon ◽  
J. Palmfeldt ◽  
A. Dürr ◽  
B. Fontaine ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Mitochondrial Matrix ◽  
Spastic Paraplegia ◽  
In Cells

scholarly journals Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum

2015 ◽  
Vol 112 (25) ◽  
pp. E3199-E3206 ◽  
Author(s):  
Kanika Bajaj Pahuja ◽  
Jinzhi Wang ◽  
Anastasia Blagoveshchenskaya ◽  
Lillian Lim ◽  
M. S. Madhusudhan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Direct Interaction ◽  
Phosphatidyl Inositol ◽  
Adaptor Proteins ◽  
Secretory Proteins ◽  
Vesicle Budding ◽  
Cargo Proteins ◽  
A Cell ◽  
Copii Vesicles ◽  
Serum Dependent

Most secretory cargo proteins in eukaryotes are synthesized in the endoplasmic reticulum and actively exported in membrane-bound vesicles that are formed by the cytosolic coat protein complex II (COPII). COPII proteins are assisted by a variety of cargo-specific adaptor proteins required for the concentration and export of secretory proteins from the endoplasmic reticulum (ER). Adaptor proteins are key regulators of cargo export, and defects in their function may result in disease phenotypes in mammals. Here we report the role of 14-3-3 proteins as a cytosolic adaptor in mediating SAC1 transport in COPII-coated vesicles. Sac1 is a phosphatidyl inositol-4 phosphate (PI4P) lipid phosphatase that undergoes serum dependent translocation between the endoplasmic reticulum and Golgi complex and controls cellular PI4P lipid levels. We developed a cell-free COPII vesicle budding reaction to examine SAC1 exit from the ER that requires COPII and at least one additional cytosolic factor, the 14-3-3 protein. Recombinant 14-3-3 protein stimulates the packaging of SAC1 into COPII vesicles and the sorting subunit of COPII, Sec24, interacts with 14-3-3. We identified a minimal sorting motif of SAC1 that is important for 14-3-3 binding and which controls SAC1 export from the ER. This LS motif is part of a 7-aa stretch, RLSNTSP, which is similar to the consensus 14-3-3 binding sequence. Homology models, based on the SAC1 structure from yeast, predict this region to be in the exposed exterior of the protein. Our data suggest a model in which the 14-3-3 protein mediates SAC1 traffic from the ER through direct interaction with a sorting signal and COPII.

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