Nondegradable ubiquitinated ATG9A organizes Golgi integrity and dynamics upon stresses

Luo, Qian; Liu, Qiangqiang; Cheng, Hongcheng; Wang, Jiale; Zhang, Tian; Zhang, Jiaojiao; Mu, Chenglong; Meng, Yuanyuan; Chen, Linbo; Zhou, Changqian; Li, Hong; Yang, Jianyu; Chen, Guo; Li, Yanjun; Pan, Leiting; Chen, Quan; Zhu, Yushan

doi:10.1016/j.celrep.2022.111195

Cited by 15 publications

(5 citation statements)

References 54 publications

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“…Interestingly, the alteration in cis‐ Golgi morphology in ATG9 KO cells is in contrast with the described role of ATG9 in preventing heat‐induced Golgi fragmentation [48]. Luo et al identified an ATG9‐GRASP55 Golgi fragmentation axis, which is distinct from the degradation of GM130 under heat stress.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Mayer,

Boeck,

Werner

et al. 2024

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Alzheimer's disease (AD) pathology is characterized by amyloid beta (Aβ) plaques and dysfunctional autophagy. Aβ is generated by sequential proteolytic cleavage of amyloid precursor protein (APP), and the site of intracellular APP processing is highly debated, which may include autophagosomes. Here, we investigated the involvement of autophagy, including the role of ATG9 in APP intracellular trafficking and processing by applying the RUSH system, which allows studying the transport of fluorescently labeled mCherry‐APP‐EGFP in a systematic way, starting from the endoplasmic reticulum. HeLa cells, expressing the RUSH mCherry‐APP‐EGFP system, were investigated by live cell imaging, immunofluorescence, and Western blot. We found that mCherry‐APP‐EGFP passed through the Golgi faster in ATG9 knockout cells. Furthermore, ATG9 deletion shifted mCherry‐APP‐EGFP from early endosomes and lysosomes toward the plasma membrane concomitant with reduced endocytosis. Importantly, this alteration in mCherry‐APP‐EGFP transport resulted in increased secreted mCherry‐soluble APP and C‐terminal fragment‐EGFP. These effects were also phenocopied by pharmacological inhibition of ULK1, indicating that autophagy is regulating the intracellular trafficking and processing of APP. These findings contribute to the understanding of the role of autophagy in APP metabolism and could potentially have implications for new therapeutic approaches for AD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Mayer,

Boeck,

Werner

et al. 2024

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“…In addition to PQC, ubiquitination of Golgi proteins regulates Golgi homeostasis, specifically Golgi structural integrity and Golgi-related vesicle trafficking. Ubiquitination induces changes in Golgi morphology during stress by inducing Golgi matrix protein degradation and disrupting the matrix by changing protein-protein interaction networks, a strategy also adopted by bacterial effector proteins ( Eisenberg-Lerner et al, 2020 ; Liu et al, 2021 ; Luo et al, 2022 ). These recent findings set the stage for an exciting new chapter in ubiquitin and Golgi research.…”

Section: Discussionmentioning

confidence: 99%

“…Current data suggest that upon overexpression of MarchIV or MarchIX, MHC-I is ubiquitinated at its short cytosolic tail, endocytosed and degraded in lysosomes ( Bartee et al, 2004 ). Upon heat stress, or inhibition of sialylation (a form of glycosylation at the Golgi), MarchIX also ubiquitinates ATG9, the only conserved TM component of the autophagy machinery at the TGN ( Luo et al, 2022 ). Ubiquitination of ATG9 induces its interaction with the Golgi structural protein GRASP55, leading to a disruption of the Golgi matrix and Golgi fragmentation ( Luo et al, 2022 ), highlighting a non-proteolytic role of ubiquitin signaling in controlling Golgi morphology during cellular stress.…”

Section: The Role Of Tm-ubiquitin Ligases At the Golgi Apparatusmentioning

confidence: 99%

“…Upon heat stress, or inhibition of sialylation (a form of glycosylation at the Golgi), MarchIX also ubiquitinates ATG9, the only conserved TM component of the autophagy machinery at the TGN ( Luo et al, 2022 ). Ubiquitination of ATG9 induces its interaction with the Golgi structural protein GRASP55, leading to a disruption of the Golgi matrix and Golgi fragmentation ( Luo et al, 2022 ), highlighting a non-proteolytic role of ubiquitin signaling in controlling Golgi morphology during cellular stress. Another RING- and B-box domain containing protein, ZFPL1, localizes to the Golgi and directly interacts with Golgi matrix protein GM130 ( Chiu et al, 2008 ; Fasimoye et al, 2022 ).…”

Section: The Role Of Tm-ubiquitin Ligases At the Golgi Apparatusmentioning

confidence: 99%

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Ubiquitin-mediated degradation at the Golgi apparatus

Buzuk

Hellerschmied

2023

Front. Mol. Biosci.

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The Golgi apparatus is an essential organelle of the secretory pathway in eukaryotic cells. It processes secretory and transmembrane proteins and orchestrates their transport to other endomembrane compartments or the plasma membrane. The Golgi apparatus thereby shapes the cell surface, controlling cell polarity, cell-cell communication, and immune signaling. The cytosolic face of the Golgi hosts and regulates signaling cascades, impacting most notably the DNA damage response and mitosis. These essential functions strongly depend on Golgi protein homeostasis and Golgi integrity. Golgi fragmentation and consequent malfunction is associated with neurodegenerative diseases and certain cancer types. Recent studies provide first insight into the critical role of ubiquitin signaling in maintaining Golgi integrity and in Golgi protein quality control. Similar to well described pathways at the endoplasmic reticulum, ubiquitin-dependent degradation of non-native proteins prevents the accumulation of toxic protein aggregates at the Golgi. Moreover, ubiquitination regulates Golgi structural rearrangements in response to cellular stress. Advances in elucidating ubiquitination and degradation events at the Golgi are starting to paint a picture of the molecular machinery underlying Golgi (protein) homeostasis.

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“…For example, it has been reported that GOLPH3, a peripheral membrane protein localized to the Golgi, is not only a Golgi stress sensor but also an initiator that transmits Golgi stress signals to the downstream pathway ( Li et al, 2016 ). ATG9A/MARCH9/GRASP55 has been suggested as a direct sensor of heat-induced Golgi stress ( Luo et al, 2022 ). Identifying common or individual sensors for these seven pathways would be essential for characterizing the Golgi stress response.…”

Section: Cellular Response To Golgi Stressmentioning

confidence: 99%

Golgi Stress Response: New Insights into the Pathogenesis and Therapeutic Targets of Human Diseases

Kim

Choi

Deshar

et al. 2023

Molecules and Cells

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The Golgi apparatus modifies and transports secretory and membrane proteins. In some instances, the production of secretory and membrane proteins exceeds the capacity of the Golgi apparatus, including vesicle trafficking and the post-translational modification of macromolecules. These proteins are not modified or delivered appropriately due to insufficiency in the Golgi function. These conditions disturb Golgi homeostasis and induce a cellular condition known as Golgi stress, causing cells to activate the 'Golgi stress response,' which is a homeostatic process to increase the capacity of the Golgi based on cellular requirements. Since the Golgi functions are diverse, several response pathways involving TFE3, HSP47, CREB3, proteoglycan, mucin, MAPK/ ETS, and PERK regulate the capacity of each Golgi function separately. Understanding the Golgi stress response is crucial for revealing the mechanisms underlying Golgi dynamics and its effect on human health because many signaling molecules are related to diseases, ranging from viral infections to fatal neurodegenerative diseases. Therefore, it is valuable to summarize and investigate the mechanisms underlying Golgi stress response in disease pathogenesis, as they may contribute to developing novel therapeutic strategies. In this review, we investigate the perturbations and stress signaling of the Golgi, as well as the therapeutic potentials of new strategies for treating Golgi stress-associated diseases.

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Nondegradable ubiquitinated ATG9A organizes Golgi integrity and dynamics upon stresses

Cited by 15 publications

References 54 publications

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Inhibition of Autophagy Alters Intracellular Transport of APP Resulting in Increased APP Processing

Ubiquitin-mediated degradation at the Golgi apparatus

Golgi Stress Response: New Insights into the Pathogenesis and Therapeutic Targets of Human Diseases

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