The flavagline FL3 interferes with the association of Annexin A2 with the eIF4F initiation complex and transiently stimulates the translation of annexin A2 mRNA

Grindheim, Ann Kari; Patil, Sudarshan; Nebigil, Canan G.; Désaubry, Laurent; Vedeler, Anni

doi:10.3389/fcell.2023.1094941

Cited by 3 publications

(7 citation statements)

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“…Interestingly, FL3, one of the PHB modulating compounds we found to decrease myelination in vitro, has been reported to cause changes in ANXA2 levels and subcellular localization (Grindheim et al, 2023).…”

Section: Discussionmentioning

confidence: 82%

“…This could indicate a role for PHB2 in the colossal cytoskeletal rearrangements required for Schwann cells to sort axons during the process of radial sorting and to wrap them in layers of myelin sheath. Interestingly, FL3, one of the PHB modulating compounds we found to decrease myelination in vitro , has been reported to cause changes in ANXA2 levels and sub-cellular localization (Grindheim et al, 2023).…”

Section: Discussionmentioning

confidence: 98%

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Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

Wilson,

Nunes,

Shen

et al. 2024

Preprint

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Schwann cells are critical for the proper development and function of the peripheral nervous system, where they form a mutually beneficial relationship with axons. Past studies have highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this work, showing that drug-mediated modulation of prohibitinsin vitrodisrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2)in vivoresults in early and severe defects in peripheral nerve development. Using a proteomic approachin vitro, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on the presence of axonal signals. Furthermore, we showin vivothat loss ofPhb2in mouse Schwann cells causes ineffective proliferation and dysregulation of transcription factors EGR2 (KROX20), POU3F1 (OCT6) and POU3F2 (BRN2) that are necessary for proper Schwann cell maturation. Schwann cell-specific deletion ofJun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the development defect seen in mice lacking Schwann cellPhb2. This work develops our understanding of Schwann cell biology, revealing thatPhb2may directly or indirectly modulate the timely expression of transcription factors necessary for proper peripheral nervous system development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

Wilson,

Nunes,

Shen

et al. 2024

Preprint

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“…This could be due to the presence of detergents in the lysates, but most likely reflects the fact that the Anxs bind to a subpopulation of mRNAs associated with the cytoskeleton fraction. Recently, we also observed the presence of AnxA2 in cap pull down mRNP complexes from the cytoskeletal fraction, but not from total lysates (Grindheim et al, 2023).…”

Section: Anxs Are Present In Mrnp Complexes Derived From Pc12 Cellsmentioning

confidence: 83%

“…All Anxs, except AnxA9 and AnxA10, have so far been found in exosomes (http://www.exocarta.org/) (Gurung et al, 2021). AnxA2 is the best characterized member of the Anx family both in terms of its association with mRNA (Vedeler and Hollas, 2000;Vedeler et al, 2012;Strand et al, 2021;Grindheim et al, 2023) and exosomes (Valapala and Vishwanatha, 2011;Desai et al, 2022). AnxA2 appears to play a role in loading RNA cargo into exosomes (Monastyrskaya, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, AnxA2 is involved in the transport of specific mRNAs to the perinuclear region for local translation (Veyrune et al, 1996;Mickleburgh et al, 2005). AnxA2 binds transiently to the eukaryotic initiation factor eIF4F thereby inhibiting translation (Grindheim et al, 2023). Thus, it may be involved in the transport of mRNAs in their silent form in a process which is regulated by its posttranslational modifications.…”

Section: Introductionmentioning

confidence: 99%

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RNA-binding is an ancient trait of the Annexin family

Patil

Panchal

Røstbø

et al. 2023

Front. Cell Dev. Biol.

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Introduction: The regulation of intracellular functions in mammalian cells involves close coordination of cellular processes. During recent years it has become evident that the sorting, trafficking and distribution of transport vesicles and mRNA granules/complexes are closely coordinated to ensure effective simultaneous handling of all components required for a specific function, thereby minimizing the use of cellular energy. Identification of proteins acting at the crossroads of such coordinated transport events will ultimately provide mechanistic details of the processes. Annexins are multifunctional proteins involved in a variety of cellular processes associated with Ca2+-regulation and lipid binding, linked to the operation of both the endocytic and exocytic pathways. Furthermore, certain Annexins have been implicated in the regulation of mRNA transport and translation. Since Annexin A2 binds specific mRNAs via its core structure and is also present in mRNP complexes, we speculated whether direct association with RNA could be a common property of the mammalian Annexin family sharing a highly similar core structure.Methods and results: Therefore, we performed spot blot and UV-crosslinking experiments to assess the mRNA binding abilities of the different Annexins, using annexin A2 and c-myc 3′UTRs as well as c-myc 5′UTR as baits. We supplemented the data with immunoblot detection of selected Annexins in mRNP complexes derived from the neuroendocrine rat PC12 cells. Furthermore, biolayer interferometry was used to determine the KD of selected Annexin-RNA interactions, which indicated distinct affinities. Amongst these Annexins, Annexin A13 and the core structures of Annexin A7, Annexin A11 bind c-myc 3′UTR with KDs in the nanomolar range. Of the selected Annexins, only Annexin A2 binds the c-myc 5′UTR indicating some selectivity.Discussion: The oldest members of the mammalian Annexin family share the ability to associate with RNA, suggesting that RNA-binding is an ancient trait of this protein family. Thus, the combined RNA- and lipid-binding properties of the Annexins make them attractive candidates to participate in coordinated long-distance transport of membrane vesicles and mRNAs regulated by Ca2+. The present screening results can thus pave the way for studies of the multifunctional Annexins in a novel cellular context.

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Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

Wilson,

Nunes,

Shen

et al. 2024

Glia

View full text Add to dashboard Cite

Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long‐term myelin maintenance and axon health, they may also be present at the Schwann cell‐axon interface during development. Here, we expand on this, showing that drug‐mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell‐specific ablation of prohibitin 2 (Phb2) in vivo results in severe defects in radial sorting and myelination. We show in vivo that Phb2‐null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell‐specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell Phb2. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2‐associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that Phb2 may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2‐mediated integration of axon signals in the Schwann cell.

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The flavagline FL3 interferes with the association of Annexin A2 with the eIF4F initiation complex and transiently stimulates the translation of annexin A2 mRNA

Cited by 3 publications

References 97 publications

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

RNA-binding is an ancient trait of the Annexin family

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

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