TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export

Stadel, Daniela; Millarte, Valentina; Tillmann, Kerstin D.; Huber, Jessica; Tamin-Yecheskel, Bat Chen; Akutsu, Masato; Demishtein, Alik; Ben‐Zeev, Bruria; Anikster, Yair; Perez, Franck; Dötsch, Volker; Elazar, Zvulun; Rogov, Vladimir V.; Farhan, Hesso; Behrends, Christian

doi:10.1016/j.molcel.2015.09.010

Cited by 118 publications

(119 citation statements)

References 31 publications

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…Amino acid starvation-induced autophagy has been demonstrated to cause the formation of Sec body from ERES in drosophila S2 cells. While we hesitate to conclude the observed increase in fluorescence intensity of ERES in actively autophagic cells is equivalent to the Sec body found in S2 cells, it is clear that autophagy also exerts an influence on the early secretory pathway in mammalian systems [28, 29]. We believe this is a mechanism to coordinates cellular secretion and autophagy, with the ultimate goal of conserving nutrients (i.e., proteins are no longer secreted out of the starved cells).…”

Section: Discussionmentioning

confidence: 88%

ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic

et al. 2017

View full text Add to dashboard Cite

BackgroundAutophagy is an inducible autodigestive process that allows cells to recycle proteins and other materials for survival during stress and nutrient deprived conditions. The kinase ULK1 is required to activate this process. ULK1 phosphorylates a number of target proteins and regulates many cellular processes including the early secretory pathway. Recently, ULK1 has been demonstrated to phosphorylate Sec16 and affects the transport of serotonin transporter at the ER exit sites (ERES), but whether ULK1 may affect the transport of other cargo proteins and general secretion has not been fully addressed.ResultsIn this study, we identified Sec23A, a component of the COPII vesicle coat, as a target of ULK1 phosphorylation. Elevated autophagy, induced by amino acid starvation, rapamycin, or overexpression of ULK1 caused aggregation of the ERES, a region of the ER dedicated for the budding of COPII vesicles. Transport of cargo proteins was also inhibited under these conditions and was retained at the ERES. ULK1 phosphorylation of Sec23A reduced the interaction between Sec23A and Sec31A. We identified serine 207, serine 312 and threonine 405 on Sec23A as ULK1 phosphorylation sites. Among these residues, serine 207, when changed to phospho-deficient and phospho-mimicking mutants, most faithfully recapitulated the above-mentioned effects of ULK1 phospho-regulation.ConclusionThese findings identify Sec23A as a new target of ULK1 and uncover a mechanism of coordinating intracellular protein transport and autophagy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-017-0138-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 88%

ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic

et al. 2017

View full text Add to dashboard Cite

show abstract

“…This has been reviewed in more detail elsewhere (Davis et al 2017). A further possible point of integration between COPII and autophagy is Tectonin β-propeller containing protein 2 [TECPR2, (Stadel et al 2015)]. TECPR2 appears to regulate the levels of Sec24 in cells and, as such, ERES function.…”

Section: Copii and Proteostasis: Autophagy And The Uprmentioning

confidence: 99%

COPII-dependent ER export in animal cells: adaptation and control for diverse cargo

McCaughey

Stephens

2018

Histochem Cell Biol

View full text Add to dashboard Cite

The export of newly synthesized proteins from the endoplasmic reticulum is fundamental to the ongoing maintenance of cell and tissue structure and function. After co-translational translocation into the ER, proteins destined for downstream intracellular compartments or secretion from the cell are sorted and packaged into transport vesicles by the COPII coat protein complex. The fundamental discovery and characterization of the pathway has now been augmented by a greater understanding of the role of COPII in diverse aspects of cell function. We now have a deep understanding of how COPII contributes to the trafficking of diverse cargoes including extracellular matrix molecules, developmental signalling proteins, and key metabolic factors such as lipoproteins. Structural and functional studies have shown that the COPII coat is both highly flexible and subject to multiple modes of regulation. This has led to new discoveries defining roles of COPII in development, autophagy, and tissue organization. Many of these newly emerging features of the canonical COPII pathway are placed in a context of procollagen secretion because of the fundamental interest in how a coat complex that typically generates 80-nm transport vesicles can package a cargo reported to be over 300 nm. Here we review the current understanding of COPII and assess the current consensus on its role in packaging diverse cargo proteins.

show abstract

“…TECPR2 depletion causes a decrease in ERES number and a delayed ER export. Maintaining a functional ERES provides a scaffold for autophagosome formation (Stadel et al, 2015). Mutations in TECPR2 leading to the translation of a truncated and unstable version of TECPR2 cause a form of HSP (Oz-Levi et al, 2012) and hereditary sensory and autonomic neuropathy (HSAN-III) (Heimer et al, 2016).…”

Section: Gene Function Classificationmentioning

confidence: 99%

“…Skin fibroblasts from TECPR2-related HSP patients show a decreased number of LC3 and P62 proteins marking a decreased autophagic flux (Oz-Levi et al, 2012). These fibroblasts also show delayed ER export (Stadel et al, 2015), an indication that the function of TECPR2 in maintaining ER export and the formation of early autophagosome intermediates is disrupted by HSP-causing mutations, presenting autophagy disruption as a likely pathomechanism in HSP neuropathy.…”

Section: Gene Function Classificationmentioning

confidence: 99%

Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies

Haidar

Timmerman

2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The inherited peripheral neuropathies (IPNs) comprise a growing list of genetically heterogeneous diseases. With mutations in more than 80 genes being reported to cause IPNs, a wide spectrum of functional consequences is expected to follow this genotypic diversity. Hence, the search for a common pathomechanism among the different phenotypes has become the holy grail of functional research into IPNs. During the last decade, studies on several affected genes have shown a direct and/or indirect correlation with autophagy. Autophagy, a cellular homeostatic process, is required for the removal of cell aggregates, long-lived proteins and dead organelles from the cell in double-membraned vesicles destined for the lysosomes. As an evolutionarily highly conserved process, autophagy is essential for the survival and proper functioning of the cell. Recently, neuronal cells have been shown to be particularly vulnerable to disruption of the autophagic pathway. Furthermore, autophagy has been shown to be affected in various common neurodegenerative diseases of both the central and the peripheral nervous system including Alzheimer’s, Parkinson’s, and Huntington’s diseases. In this review we provide an overview of the genes involved in hereditary neuropathies which are linked to autophagy and we propose the disruption of the autophagic flux as an emerging common pathomechanism. We also shed light on the different steps of the autophagy pathway linked to these genes. Finally, we review the concept of autophagy being a therapeutic target in IPNs, and the possibilities and challenges of this pathway-specific targeting.

show abstract

TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export

Cited by 118 publications

References 31 publications

ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic

ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic

COPII-dependent ER export in animal cells: adaptation and control for diverse cargo

Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies

Contact Info

Product

Resources

About