Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

Paul, Bindu D.

doi:10.3390/antiox10091468

Cited by 10 publications

(3 citation statements)

References 103 publications

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“…The IRE branch was not significantly affected by PKM2 knockdown, whereas the phosphorylation and protein levels of PERK were markedly reduced, indicating that the UPR was not activated but rather suppressed by PKM2 knockdown. It has been reported that the PERK pathway is involved in not only ER stress but also Golgi stress [55,56]. However, the ER-resident chaperon Bip is induced only by the UPR and not by the Golgi stress response [49,55].…”

Section: Resultsmentioning

confidence: 99%

PKM2 controls the translation of TFE3 to maintain the integrity of the Golgi apparatus for the survival of HeLa and ME‐180 cervical cancer cells

2023

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The M2 isoform of pyruvate kinase (PKM2) is abundantly expressed in various cancer cells and associated with tumorigenesis, tumour proliferation and tumour progression. However, the role of PKM2 in these oncological processes is not fully understood. In the present study, we depleted PKM2 expression using RNA interference (RNAi), which induced apoptotic cell death and was accompanied by the downregulation of GM130, giantin, and p115 in HeLa and ME‐180 cervical cancer cells. The decreased expression of these proteins caused structural and functional disturbances in the Golgi apparatus, which manifested as the dispersion of the Golgi apparatus and delayed anterograde trafficking from the ER to the Golgi. The transcription factor, TFE3, which functions in the Golgi stress response, was responsible for the expression of GM130, giantin, and p115 that maintained the integrity of the organelle under normal growth conditions. In PKM2‐knockdown cells, the translation of TFE3 was markedly reduced. Knockdown of TFE3 by RNAi resulted in the downregulation of GM130, giantin, and p115, dispersion of the Golgi apparatus, and apoptotic cell death, similar to those observed following PKM2 knockdown. Conversely, the exogenous expression of TFE3 in PKM2 knockdown cells partially mitigated the aforementioned effects. We also demonstrated that PKM2 bound to the 5′ UTR on TFE3 mRNA and promoted translation. This study is the first to identify a new function for PKM2, which activates the basal Golgi stress response to maintain the integrity of the Golgi apparatus through the translation of TFE3 and promote cancer cell survival.

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Section: Resultsmentioning

confidence: 99%

PKM2 controls the translation of TFE3 to maintain the integrity of the Golgi apparatus for the survival of HeLa and ME‐180 cervical cancer cells

2023

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“…Additionally, other groups have reported a suboptimal expression and activity of the transporters for cystine and cysteine, respectively [ 15 , 34 ]. We have also shown that cysteine homeostasis is linked to stress responses such as the oxidative stress response, organellar stress responses such as the ER stress response, and to the Golgi stress response [ 9 , 11 , 16 , 35 , 36 ]. CSE is an inducible protein and is highly sensitive to stress stimuli, with its response being compromised in HD.…”

Section: Discussionmentioning

confidence: 99%

Mutant Huntingtin Derails Cysteine Metabolism in Huntington’s Disease at Both Transcriptional and Post-Translational Levels

2022

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Cysteine is a semi-essential amino acid that not only plays an essential role as a component of protein synthesis, but also in the generation of numerous sulfur-containing molecules such as the antioxidant glutathione and coenzyme A. We previously showed that the metabolism of cysteine is dysregulated in Huntington’s disease (HD), a neurodegenerative disorder triggered by the expansion of polyglutamine repeats in the protein huntingtin. In this study, we showed that cysteine metabolism is compromised at multiple levels in HD, both transcriptional and post-translational. Accordingly, restoring cysteine homeostasis may be beneficial in HD.

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“…This also leads to significant changes in the trafficking of vesicles between the Golgi and the ER and in protein secretion. To support these changes Golgi proteins are up-regulated and some of these are structural or mediators of vesicle trafficking [ 67–70 ]. Recent studies have linked the Golgi apparatus as an organelle able to control mTOR signalling directly, in addition to the tight regulation of mTOR signalling and cell proliferation by the lysosome [ 71–73 ].…”

Section: Introductionmentioning

confidence: 99%

The role of CaMKK2 in Golgi-associated vesicle trafficking

Kennedy

Gibson

O'Hare

et al. 2023

Biochemical Society Transactions

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Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular processes within the cell that regulate energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by the activation of downstream kinases, AMP-activated protein kinase (AMPK) and other calcium/calmodulin-dependent protein kinases. Consequently, its deregulation has a role in multiple human metabolic diseases including obesity and cancer. Despite the importance of CaMKK2, its signalling pathways and pathological mechanisms are not completely understood. Recent work has been aimed at broadening our understanding of the biological functions of CaMKK2. These studies have uncovered new interaction partners that have led to the description of new functions that include lipogenesis and Golgi vesicle trafficking. Here, we review recent insights into the role of CaMKK2 in membrane trafficking mechanisms and discuss the functional implications in a cellular context and for disease.

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Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease

Cited by 10 publications

References 103 publications

PKM2 controls the translation of TFE3 to maintain the integrity of the Golgi apparatus for the survival of HeLa and ME‐180 cervical cancer cells

PKM2 controls the translation of TFE3 to maintain the integrity of the Golgi apparatus for the survival of HeLa and ME‐180 cervical cancer cells

Mutant Huntingtin Derails Cysteine Metabolism in Huntington’s Disease at Both Transcriptional and Post-Translational Levels

The role of CaMKK2 in Golgi-associated vesicle trafficking

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