Gigaxonin is required for intermediate filament transport

Bhuvanasundar Renganathan, James P Zewe, Yuan Cheng, Mark Kittisopikul, Puneet Opal, Karen M Ridge, Vladimir I. Gelfand

Preprint posted on 20 August 2022

Article now published in The FASEB Journal at

Who is the culprit? Check out this preprint which demonstrates why intermediate filaments aggregate in neuronal disorders.

Selected by Suganya Sivagurunathan

Categories: cell biology


Vimentin, an intermediate filament (IF) protein, has long been associated with cell migration (Eckes et al., 2000), metastasis and is a well-known marker for epithelial-to-mesenchymal transition (Kalluri & Weinberg, 2009). Vimentin-null cells are slower in their movements (Eckes et al., 2000) and their DNA is damaged when the cells go through constricted spaces (Patteson et al., 2019). Presence of vimentin in a cell also makes the cytoplasm stiffer and recent reports show that localization of vimentin in the cortex, along with actin, impacts cortical stiffness as well (Guo et al., 2013; Vahabikashi et al., 2019; Wu et al., 2021). Furthermore, it has been shown how the organization of vimentin plays an important role in controlling cell motility (Helfand et al., 2011). In certain disease conditions, such as Giant axonal Neuropathy, the architecture of vimentin is severely affected in neuronal and non-neuronal cells. The vimentin intermediate filaments (VIFs) are not extended until the cell periphery anymore and aggregate near the perinuclear region (Mahammad et al., 2013). Although earlier reports have identified the aggregation of VIFs in the perinuclear region in Giant axonal neuropathic conditions, the mechanisms behind this unusual VIF organization have not been explored. This preprint addresses the cause of aggregation and the possible ways it could happen.


Key findings


Altered dynamics of vimentin upon knockout of GAN

Since mutations in the gigaxonin (GAN) gene – which encodes an adaptor protein for E3 ubiquitin ligase substrates – cause Giant axonal neuropathy, the authors used GAN knockout cells in their study. Gigaxonin has been shown to maintain the turnover of IFs. The authors took advantage of photoconversion to show that the dynamics of filaments is disturbed in GAN null conditions. Vimentin was tagged with mEOS 3.2 and photoconversion of these tagged proteins in GAN KO cells showed that the movement of the protein was totally restricted, unlike what could be observed in the control cells. The authors also confirmed that this effect was not cell specific by performing these experiments in a different cell line as well.


GAN loss impacts dynamics of neurofilaments

The loss of GAN not only disturbed the organization of vimentin, but also increased its soluble fraction. Vimentin was not the only intermediate filament protein that was affected by the loss of GAN. The neurofilaments, major intermediate filament proteins in neuronal cells, also seemed to be severely impacted under this condition. The authors investigated the dynamics of neurofilaments in neuronal GAN KO cells using their photoconversion technique, which showed that the transport of neurofilaments was also disrupted.


Kinesin-1 is not the culprit

Vimentin and other intermediate filament proteins are transported inside the cell by the microtubule motor, kinesin-1. To investigate whether the dynamics of other cargo of kinesin-1 had been impacted in the GAN null condition, the authors tested the transport of mitochondria, lysosomes and autophagosomes. Interestingly, the transport of lysosomes and autophagosomes was unaffected by loss of GAN, confirming that kinesin-1 was still functional. The authors reasoned that the abnormalities in the transport of mitochondria were due to its binding with the immotile intermediate filaments. The authors hypothesized that vimentin might be interacting with kinesin-1 through an adaptor protein and that the increase in soluble oligomers as a result of the loss of GAN might sequester this adaptor protein, which thereby disturbs the dynamics of intermediate filaments (Fig 6 in the preprint).


What I like about the preprint/why I think this new work is important.


            This preprint is interesting to me since I am trying to understand how vimentin influences the dynamics of cells/ cell migration, and the authors here show the altered dynamics of the cytoskeletal protein itself in the context of a neurological disorder. This preprint provides a new perspective on the possible dynamics of vimentin during cell migration. Will the transport of vimentin be restricted to a certain region of the cell to enable the cells to migrate easily?


What I think is the most interesting part of this work is how the authors have used the photoconversion strategy to show the dynamics of intermediate filaments. Although the perinuclear aggregation of intermediate filaments in Giant Axonal Neuropathy is well known, an important novel aspect revealed by this work is that the transport of intermediate filaments itself is affected. And it is interesting to see how kinesin-1 is not the reason behind the abnormal dynamics of intermediate filaments.



Questions for the authors.


  1. Does phosphorylation play a role in the abnormal dynamics of intermediate filaments?
  2. Will any other protein that is under the control of GAN for its degradation influence the accumulation of intermediate filaments?


Eckes, B., Colucci-Guyon, E., Smola, H., Nodder, S., Babinet, C., Krieg, T., & Martin, P. (2000). Impaired wound healing in embryonic and adult mice lacking vimentin. Journal of Cell Science, 113 ( Pt 13)(13), 2455–2462.

Guo, M., Ehrlicher, A. J., Mahammad, S., Fabich, H., Jensen, M. H., Moore, J. R., Fredberg, J. J., Goldman, R. D., & Weitz, D. A. (2013). The role of vimentin intermediate filaments in cortical and cytoplasmic mechanics. Biophysical Journal, 105(7), 1562–1568.

Helfand, B. T., Mendez, M. G., Murthy, S. N. P., Shumaker, D. K., Grin, B., Mahammad, S., Aebi, U., Wedig, T., Wu, Y. I., Hahn, K. M., Inagaki, M., Herrmann, H., & Goldman, R. D. (2011). Vimentin organization modulates the formation of lamellipodia. Molecular Biology of the Cell, 22(8), 1274–1289.

Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. The Journal of Clinical Investigation, 119(6), 1420–1428.

Mahammad, S., Prasanna Murthy, S. N., Didonna, A., Grin, B., Israeli, E., Perrot, R., Bomont, P., Julien, J. P., Kuczmarski, E., Opal, P., & Goldman, R. D. (2013). Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation. The Journal of Clinical Investigation, 123(5), 1964–1975.

Patteson, A. E., Vahabikashi, A., Pogoda, K., Adam, S. A., Mandal, K., Kittisopikul, M., Sivagurunathan, S., Goldman, A., Goldman, R. D., & Janmey, P. A. (2019). Vimentin protects cells against nuclear rupture and DNA damage during migration. Journal of Cell Biology, 218(12), 4079–4092.

Vahabikashi, A., Park, C. Y., Perkumas, K., Zhang, Z., Deurloo, E. K., Wu, H., Weitz, D. A., Stamer, W. D., Goldman, R. D., Fredberg, J. J., & Johnson, M. (2019). Probe Sensitivity to Cortical versus Intracellular Cytoskeletal Network Stiffness. Biophysical Journal, 116(3), 518–529.

Wu, H., Shen, Y., Sivagurunathan, S., Weber, M. S., Adam, S. A., Shin, J. H., Fredberg, J. J., Medalia, O., Goldman, R., & Weitz, D. A. (2021). Vimentin Intermediate Filaments and Filamentous Actin Form Unexpected Interpenetrating Networks That Redefine the Cell Cortex. BioRxiv, 2021.07.29.454155.


Posted on: 1 November 2022


Read preprint (1 votes)

Author's response

Bhuvanasundar Renganathan shared

  1. The phosphorylation status of intermediate filaments (IF) is critical for their assembly. When IFs are phosphorylated, they disassemble insoluble filaments and release soluble oligomers into the cytosol. Our findings suggest that when gigaxonin is lost, soluble IF increases. Based on current knowledge about IF assembly & disassembly in normal cells we can assume that augmented soluble IF in the GAN disorder will have higher phosphorylation levels. It is unknown how phosphorylation influences IF dynamics mechanistically. Indeed, an avenue to be investigated in depth.

  2. There could be other proteins manifested in the poor dynamics of intermediate filament in GAN disorder. We have hypothesized that loss of a potential adaptor protein which link intermediate filaments to kinesin-1 motor could be the reason for the accumulation.  From the literature, we know that gigaxonin interacts with ubiquitin and heat shock proteins in addition to intermediate filaments (Johnson-Kerner, B. L. et al).  And gigaxonin regulates the ATG16L1 protein, which is involved in autophagosome synthesis (Scrivo, A et al).  Identifying the various interactions of the gigaxonin protein will provide a comprehensive understanding of the disorder.


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