ER as master regulator of membrane trafficking and organelle function

Wenzel, Eva M.; Elfmark, Liv Anker; Stenmark, Harald; Raiborg, Camilla

doi:10.1083/jcb.202205135

Cited by 56 publications

(27 citation statements)

References 203 publications

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“…Multi-organelle interactions were recently identified in the division of mitochondria 17,19 and endosomes 18 , further suggesting that membrane fission events are highly coordinated processes requiring the involvement of multiple organelles. In all these cases, the ER appears to be the common organelle, thus supporting the idea that the ER may regulate contact between different organelles 19,49 .…”

Section: Discussionsupporting

confidence: 62%

Arf1-PI4KIIIβ positive vesicles regulate phosphatidylinositol-3-phosphate signalling to facilitate the fission of lysosomal tubules

Boutry

DiGiovanni

Demers

et al. 2023

Preprint

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Formation and fission of tubules from lysosomal organelles, such as autolysosomes, endolysosomes or phagolysosomes, are required for lysosome reformation. However, the mechanisms governing these processes in the different forms of lysosomal organelles are poorly understood. For instance, the role of phosphatidylinositol-4-phosphate (PI(4)P) is unclear as it was shown to promote the formation of tubules from phagolysosomes but was proposed to inhibit tubule formation on autolysosomes because the loss of PI4KIIIβ causes extensive lysosomal tubulations. Using super-resolution live-cell imaging, we show that Arf1-PI4KIIIβ positive vesicles are recruited to tubule fission sites from autolysosomes, endolysosomes and phagolysosomes. Moreover, we show that PI(4)P is required to form autolysosomal tubules and that increased lysosomal tubulation caused by loss of PI4KIIIβ represents impaired tubule fission. At the site of fission, we propose that Arf1-PI4KIIIβ positive vesicles mediate a PI(3)P signal on lysosomes in a process requiring the lipid transfer protein SEC14L2. Our findings indicate that Arf1-PI4KIIIβ positive vesicles and their regulation of PI(3)P are critical components of the lysosomal tubule fission machinery.

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Section: Discussionsupporting

confidence: 62%

Arf1-PI4KIIIβ positive vesicles regulate phosphatidylinositol-3-phosphate signalling to facilitate the fission of lysosomal tubules

Boutry

DiGiovanni

Demers

et al. 2023

Preprint

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“…The most obvious function would be to recruit PtdIns4P‐binding proteins like ORP9, ORP10, ORP11, and ORP1L to establish contacts with the ER via the VAP‐binding domains of the ORP proteins. However, elegant work on ER–Golgi contacts has revealed an additional function for PtdIns4P in membrane contact sites, namely, in driving cholesterol transfer (Wenzel et al , 2022). In particular, OSBP has been shown to transfer cholesterol from ER to Golgi membranes in exchange for PtdIns4P, and dephosphorylation of PtdIns4P in the ER membrane serves to maintain a concentration gradient that drives the exchange (Mesmin et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair

et al. 2022

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Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP-ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol-PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.

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“…The ability to recognize cellular stress and trigger adaptive host defenses has been indispensable throughout evolution. As a cellular organelle that controls protein quality and distinguishes attacks on protein fidelity, the ER holds a unique position in the cell ( 43 , 44 ). It has been previously shown that UPR activation regulates cell cycle progression ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Giardia duodenalis-induced G0/G1 intestinal epithelial cell cycle arrest and apoptosis involve activation of endoplasmic reticulum stress in vitro

Zhao

Qin

et al. 2023

Front. Immunol.

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Giardia duodenalis is a zoonotic intestinal protozoan parasite that may cause host diarrhea and chronic gastroenteritis, resulting in great economic losses annually and representing a significant public health burden across the world. However, thus far, our knowledge on the pathogenesis of Giardia and the related host cell responses is still extensively limited. The aim of this study is to assess the role of endoplasmic reticulum (ER) stress in regulating G0/G1 cell cycle arrest and apoptosis during in vitro infection of intestinal epithelial cells (IECs) with Giardia. The results showed that the mRNA levels of ER chaperone proteins and ER-associated degradation genes were increased and the expression levels of the main unfolded protein response (UPR)-related proteins (GRP78, p-PERK, ATF4, CHOP, p-IRE1, XBP1s and ATF6) were increased upon Giardia exposure. In addition, cell cycle arrest was determined to be induced by UPR signaling pathways (IRE1, PERK and ATF6) through upregulation of p21 and p27 levels and promotion of E2F1-RB complex formation. Upregulation of p21 and p27 expression was shown to be related to Ufd1-Skp2 signaling. Therefore, the cell cycle arrest was induced by ER stress when infected with Giardia. Furthermore, the apoptosis of the host cell was also assessed after exposure to Giardia. The results indicated that apoptosis would be promoted by UPR signaling (PERK and ATF6), but would be suppressed by the hyperphosphorylation of AKT and hypophosphorylation of JNK that were modulated by IRE1 pathway. Taken together, both of the cell cycle arrest and apoptosis of IECs induced by Giardia exposure involved the activation of the UPR signaling. The findings of this study will deepen our understanding of the pathogenesis of Giardia and the associated regulatory network.

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ER as master regulator of membrane trafficking and organelle function

Cited by 56 publications

References 203 publications

Arf1-PI4KIIIβ positive vesicles regulate phosphatidylinositol-3-phosphate signalling to facilitate the fission of lysosomal tubules

Arf1-PI4KIIIβ positive vesicles regulate phosphatidylinositol-3-phosphate signalling to facilitate the fission of lysosomal tubules

Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair

Giardia duodenalis-induced G0/G1 intestinal epithelial cell cycle arrest and apoptosis involve activation of endoplasmic reticulum stress in vitro

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