ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER

Costello, Joseph L.; Castro, Inês G.; Hacker, Christian; Schrader, Tina A.; Metz, Jeremy; Zeuschner, Dagmar; Azadi, Afsoon S.; Godinho, Luís F.; Costina, Victor; Findeisen, Peter; Manner, Andreas; Islinger, Markus; Schrader, Michael

doi:10.1083/jcb.201607055

Cited by 199 publications

(291 citation statements)

References 50 publications

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“…As it is unlikely that the globular peroxisome on its own can provide sufficient membrane lipids to generate such a protrusion, additional membrane lipids are likely provided by the ER. In support of this, we have recently revealed that peroxisome‐ER membrane contacts have an impact on peroxisomal membrane expansion 46. Whereas protrusions were not observed in control fibroblasts, they were formed in PEX5 and PEX14 deficient cells under control conditions, albeit more frequently in PEX5 deficient cells (Figure 3E).…”

Section: Resultssupporting

confidence: 69%

“…This untethered motion is observed in COS‐7 cells, where MIRO1 expression accumulates peroxisomes in the cell periphery where microtubule‐plus ends are located (Figures 1 and 4B). We recently revealed that peroxisome‐ER membrane contacts are mediated by peroxisomal ACBD5 that interacts with ER‐resident VAPB to form a peroxisome‐ER tether 46. Loss of ACBD5 increased the movement of peroxisomes in human skin fibroblasts, indicating that peroxisome‐ER membrane contacts restrict peroxisome motility.…”

Section: Resultsmentioning

confidence: 99%

“…These structures resemble the globular peroxisomes and protrusions induced by MIRO1 via microtubule‐dependent motor forces. Globular peroxisomes can become more static, either by docking to microtubules and/or tethering to other organelles such as the ER (66.2% ± 2.6% of peroxisomes in COS‐7 cells are associated with the ER46; Figure 5C 42‐54 seconds; Video S10). However, in contrast to the more static globular peroxisomes, the membrane protrusions show a more random, tentacle‐like movement, which does not seem to be directed by microtubules (Figure 5C 42‐54 seconds; Video S10).…”

Section: Resultsmentioning

confidence: 99%

“…Peroxisomes were automatically detected and tracked using a customised in‐house algorithm 41, 46. Briefly, each image was filtered using a scale‐space Laplace of Gaussian filtering approach58, 59 over scales corresponding to the size range of peroxisomes.…”

Section: Methodsmentioning

confidence: 99%

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A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes

Castro

Richards

Metz

et al. 2018

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Peroxisomes are dynamic organelles which fulfil essential roles in lipid and ROS metabolism. Peroxisome movement and positioning allows interaction with other organelles and is crucial for their cellular function. In mammalian cells, such movement is microtubule‐dependent and mediated by kinesin and dynein motors. The mechanisms of motor recruitment to peroxisomes are largely unknown, as well as the role this plays in peroxisome membrane dynamics and proliferation. Here, using a combination of microscopy, live‐cell imaging analysis and mathematical modelling, we identify a role for Mitochondrial Rho GTPase 1 (MIRO1) as an adaptor for microtubule‐dependent peroxisome motility in mammalian cells. We show that MIRO1 is targeted to peroxisomes and alters their distribution and motility. Using a peroxisome‐targeted MIRO1 fusion protein, we demonstrate that MIRO1‐mediated pulling forces contribute to peroxisome membrane elongation and proliferation in cellular models of peroxisome disease. Our findings reveal a molecular mechanism for establishing peroxisome‐motor protein associations in mammalian cells and provide new insights into peroxisome membrane dynamics in health and disease.

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes

Castro

Richards

Metz

et al. 2018

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“…To enable these adaptations, peroxisomes move along cytoskeletal tracks, a process which likely facilitates their metabolic interaction with other organelles and assists in their membrane expansion and division pathways [8]. …”

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confidence: 99%

Miro1 – the missing link to peroxisome motility

Castro

Schrader

2018

Communicative & Integrative Biology

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Peroxisomes are ubiquitous, highly dynamic, multifunctional compartments in eukaryotic cells, which perform key roles in cellular lipid metabolism and redox balance. Like other membrane-bound organelles, peroxisomes must move in the cellular landscape to perform localized functions, interact with other organelles and to properly distribute during cell division. However, our current knowledge of peroxisome motility in mammalian cells is still very limited. Recently, three independent studies have identified Miro1 as a regulator of peroxisome motility in mammalian cells. In these studies, the authors show that Miro1 is targeted to peroxisomes in several cell lines, in a process that relies on its interaction with the peroxisomal chaperone Pex19. Interestingly, however, different conclusions are drawn about which Miro1 isoforms are targeted to peroxisomes, how it interacts with Pex19 and most importantly, the type of motility Miro1 is regulating.

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The peroxisome biogenesis factors Pex3 and Pex19: multitasking proteins with disputed functions

Jansen

Klei

2019

FEBS Letters

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The peroxisomal membrane protein (PMP) Pex3 and its cytosolic interaction partner Pex19 have been implicated in peroxisomal membrane biogenesis. Although these peroxins have been extensively studied, no consensus has been reached yet on how they operate. Here, we discuss two major models of their function, namely, in direct insertion of proteins into the peroxisomal membrane or in formation of PMP‐containing vesicles from the endoplasmic reticulum (ER). Pex3 can also recruit other proteins to the peroxisomal membrane (e.g., Inp1, Atg30, Atg36), thereby fulfilling roles in other processes such as autophagy and organelle retention. Recent studies indicate that Pex3 and Pex19 can also facilitate sorting of certain membrane proteins to other cellular organelles, including the ER, lipid droplets, and mitochondria.

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ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER

Abstract: Costello et al. identify ACBD5 and VAPB as key components of a peroxisome–ER tether in mammalian cells. Disruption of this tethering complex leads to reduced peroxisomal membrane expansion and increased peroxisomal movement.

Cited by 199 publications

References 50 publications

A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes

A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes

Miro1 – the missing link to peroxisome motility

The peroxisome biogenesis factors Pex3 and Pex19: multitasking proteins with disputed functions

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