Biophysical and molecular mechanisms of ESCRT functions, and their implications for disease

Migliano, Simona M.; Wenzel, Eva M.; Stenmark, Harald

doi:10.1016/j.ceb.2022.01.007

Cited by 42 publications

(34 citation statements)

References 69 publications

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“…First, the protein tyrosine phosphatase 1B (PTP1B), which is embedded in the cytoplasmic face of the ER, dephosphorylates EGFRs on the endosomes, depending on Annexin A1/S100A11-mediated ER–endosome contact sites ( Eden et al, 2010 ). At the same time, the EGFRs are sorted into forming ILVs by the ESCRT protein machinery, which interacts with the ubiquitinated EGFRs and mediates membrane deformation and scission to generate ILVs ( Migliano et al, 2022 ). Interestingly, the ESCRT proteins HRS and STAM are dephosphorylated by PTP1B, implying that the Annexin A1/S100A11-mediated ER–endosome contact sites can regulate ESCRT function ( Eden et al, 2010 ; Stuible et al, 2010 ).…”

Section: Er In Control Of Endosomesmentioning

confidence: 99%

ER as master regulator of membrane trafficking and organelle function

Wenzel

Elfmark

Stenmark

et al. 2022

Journal of Cell Biology

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The endoplasmic reticulum (ER), which occupies a large portion of the cytoplasm, is the cell’s main site for the biosynthesis of lipids and carbohydrate conjugates, and it is essential for folding, assembly, and biosynthetic transport of secreted proteins and integral membrane proteins. The discovery of abundant membrane contact sites (MCSs) between the ER and other membrane compartments has revealed that, in addition to its biosynthetic and secretory functions, the ER plays key roles in the regulation of organelle dynamics and functions. In this review, we will discuss how the ER regulates endosomes, lysosomes, autophagosomes, mitochondria, peroxisomes, and the Golgi apparatus via MCSs. Such regulation occurs via lipid and Ca2+ transfer and also via control of in trans dephosphorylation reactions and organelle motility, positioning, fusion, and fission. The diverse controls of other organelles via MCSs manifest the ER as master regulator of organelle biology.

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Section: Er In Control Of Endosomesmentioning

confidence: 99%

ER as master regulator of membrane trafficking and organelle function

Wenzel

Elfmark

Stenmark

et al. 2022

Journal of Cell Biology

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“…Functions range from the formation of multivesicular bodies (MVBs) in the endosomal sorting pathway [2], virus budding [3], and cytokinetic abscission [4], to nuclear envelope surveillance and reformation [5][6][7], autophagosome closure [8], and plasma-membrane [9] and lysosome membrane repair [10,11]. ESCRT biology and functions are described in detail in comprehensive recent reviews [12][13][14][15]. In the present review we will focus on the molecular mechanisms of this machinery, highlighting ESCRT roles in membrane remodeling, repair, and sealing.…”

Section: Introductionmentioning

confidence: 99%

The ESCRT Machinery: Remodeling, Repairing, and Sealing Membranes

Olmos

2022

Membranes

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The ESCRT machinery is an evolutionarily conserved membrane remodeling complex that is used by the cell to perform reverse membrane scission in essential processes like protein degradation, cell division, and release of enveloped retroviruses. ESCRT-III, together with the AAA ATPase VPS4, harbors the main remodeling and scission function of the ESCRT machinery, whereas early-acting ESCRTs mainly contribute to protein sorting and ESCRT-III recruitment through association with upstream targeting factors. Here, we review recent advances in our understanding of the molecular mechanisms that underlie membrane constriction and scission by ESCRT-III and describe the involvement of this machinery in the sealing and repairing of damaged cellular membranes, a key function to preserve cellular viability and organellar function.

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“…Through the MIT domain, spastin is able to interact with components of the ESCRT-III machinery (Reid et al, 2005, Yang et al, 2008). Through these interactions, spastin is involved in endosome formation and processing, nuclear envelope reformation, and midbody abscission during cytokinesis (reviewed in (Migliano et al, 2022)). ESCRT-III recruits spastin to the midbody during mitotic cytokinesis in HeLa cells to sever the midbody microtubules and allow the completion of membrane fission (Connell et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

Cheers

O’Connor

Johnson

et al. 2022

Preprint

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The development and function of male gametes is critically dependent on a dynamic microtubule network, yet how this is regulated remains poorly understood. We have recently shown that microtubule severing, via the action of the meiotic AAA ATPase protein clade, plays a critical role in this process. Here, we sought to elucidate the roles of spastin, an as yet unexplored member of this clade in spermatogenesis. Using a SpastKO/KO mouse model, we reveal that spastin loss resulted in a complete loss of functional germ cells. Spastin plays a critical role in the assembly and function of the male meiotic spindle, and in its absence, apoptosis is significantly increased. Consistent with meiotic failure, round spermatid nuclei were enlarged, indicating aneuploidy, but were still able to enter spermiogenesis. During spermiogenesis, we observed extreme abnormalities in manchette structure, supernumerary acrosome formation, and commonly, a loss of nuclear integrity. This work defines a novel and essential role for spastin in regulating microtubule dynamics during spermatogenesis and is of potential relevance to patients carrying Spastin variants and to the medically assisted reproductive technology industry.

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Biophysical and molecular mechanisms of ESCRT functions, and their implications for disease

Cited by 42 publications

References 69 publications

ER as master regulator of membrane trafficking and organelle function

ER as master regulator of membrane trafficking and organelle function

The ESCRT Machinery: Remodeling, Repairing, and Sealing Membranes

Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity

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