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VIDEO: Carlos Castañeda on Ubiquitin-Mediated Phase Transitions in Protein Quality Control

Author
Jill Bouchard

Managing editor, Condensates.com

Type Kitchen Table Talk
Topics
Keywords

Dewpoint and Condensates.com welcomed Carlos Castañeda from Syracuse University for an incredibly thought-provoking talk on April 28 as part of our Kitchen Table Talk series. Carlos has extensive experience in protein quality control. He obtained his PhD in Molecular and Computational Biophysics from Johns Hopkins University, studied with David Fushman at the University of Maryland during his postdoc, and became a professor at Syracuse in 2014. In that time, he biophysically characterized ubiquitin linkages, developed enzymatic methods to study ubiquitination, and determined how ubiquitin modulates phase behavior.

Carlos has mastered the use of a wide range of biochemical, biophysical, and cell biology methods to carefully tease apart the molecular mechanisms that drive protein quality control. The Castañeda lab showed how ubiquitin can modulate phase transitions in a way that may release proteins stuck in stress granules so they can be sent for degradation by the proteasome. And they have gone on to show how this phase behavior is important for neurodegeneration by determining the effects of ALS-mutations in vitro and in cells.

In his talk, Carlos shares all the molecular details that allows some polyubiquitin chains to modulate phase separation more than others. We were all fully immersed in his talk and many attendees had great questions and hung around for a lively discussion afterward. Carlos also generously provided written answers to all questions he didn’t have time to answer during the show—you can find those here. Enjoy this thought-provoking talk and discussion in our recording of the event below. And if you want to start or continue a conversation with Carlos, he welcomes emails at cacastan@syr.edu.

Carlos Castañeda on Ubiquitin-Mediated Phase Transitions in Protein Quality Control


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TRANSCRIPT

Jill Bouchard (00:00:00):
So without further ado, it’s my great pleasure to introduce today’s speaker and my former collaborator, Carlos Castaneda, from Syracuse University. Carlos got his PhD in Molecular and Computational Physics, from Johns Hopkins University. For his postdoc, he studied with David Fushman, at the University of Maryland. And he became a Professor at Syracuse, in 2014. He’s done quite a bit of work in the field of protein quality control, including biophysical characterization of ubiquitin linkages, developing enzymatic methods to study ubiquitin and best of all, determining how ubiquitin modulates phase behavior.

Jill Bouchard (00:00:35):
In fact, Carlos’s lab, along with some of my former colleagues from the Taylor Lab, at St. Jude, showed how ubiquitin can modulate phase transitions of a proteasome shuttle protein. And this may be a mechanism that releases protein stuck in stress granules, so they can be sent for degradation. And when I was in the Mittag Lab, at St. Jude, I was fortunate to join some of these efforts, in understanding ubiquitin modulated phase separation, as well.

Jill Bouchard (00:01:00):
And the Castaneda Lab has also gone on to show how neurodegenerative disease mutations affect phase behavior. And somehow, Carlos has managed to do all this, during a pandemic, with three kids under the age of five! We commend you. And Carlos’s lab techniques are equally impressive. His lab uses a wide range of biochemical, biophysical, and cell biology methods, to carefully tease apart the molecular mechanisms underlying all the complex interactions involved in protein quality control. And I’ll let Carlos fill you in on all those fascinating details. So Carlos, thanks again for joining us. We’re so excited to hear your story about ubiquitin-mediated phase transitions in protein quality control. The floor is yours.

Carlos Castañeda (00:01:44):
Thank you so much, Jill. That was quite the introduction. I don’t even know how to begin after hearing all of that, but I think a lot of you just heard the first part of my talk, so great. No, I really want to thank Jill. I do want to think Dewpoint Therapeutics, as well, for giving me the opportunity and giving us, really, the opportunity to tell you about some of our recent work that is unpublished but particularly, looking at the role of ubiquitin and also polyubiquitin chains, on how they modulate phase behavior of the shuttle protein that’s involved in protein quality control, called UBQLN2…

EXTENDED Q&A

Question from Elliot Dine: What are the dynamics of UBQLN2 recruitment to SG? Does it match the dynamics of Ub and Ub linkages in SG?
Carlos’ Response: This is a very good and complicated question to answer. Cellular localization of UBQLN2 appears dependent on concentration. Endogenously expressed UBQLN2 are found in stress granules but exogenously-introduced (overexpressed) UBQLN2 form UBQLN2-bodies that do not colocalize with stress granule markers. These bodies can sometimes form without stress (aside from the stress of having to deal with transfected DNA). We are actively working on approaches to elucidate dynamics of endogenous UBQLN2 in stress granules, and polyUb in turn…

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