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Publications of the Week

HDAC6 Mediates an Aggresome-Like Mechanism for NLRP3 and Pyrin Inflammasome Activation

By September 28, 2020No Comments

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This week we profile a recent publication in Science from Dr. Venkat Magupalli (pictured, back row, 6th from left) and
Dr. Roberto Negro (back, 4th from left) in the laboratory of Dr. Hao Wu (front, 5th from left) at Harvard Medical School.

Can you provide a brief overview of your lab’s current research focus?

The Wu laboratory of mechanistic immunology focuses on elucidating the molecular and cellular mechanisms that govern the assembly, regulation and therapeutic intervention of supramolecular complexes in innate immunity. Our current research focuses on inflammasomes, which are cellular machineries for activating inflammatory caspases. Activated caspases process the IL-1 family cytokines and the pore forming protein gasdermin D (GSDMD), and GSDMD pores release the mature cytokines and cause pyroptotic cell death. We also have ongoing projects on mechanism and therapeutic intervention in tumor necrosis factor (TNF) and Toll-like receptor (TLR) signaling pathways.

There are three pillars for the research in the lab, 1) cryo-EM and other biophysical methods for detailed understanding of molecular complexes, including a large number of membrane proteins, 2) drug screening and validation for potential therapeutics in immune diseases and cancer, and 3) cellular imaging and other tools for the assembly of supramolecular complexes in cells.

What is the significance of the findings in this publication?

Canonical inflammasomes are multicomponent protein complexes that play key roles in immune surveillance of infections and danger by activating caspase-1, which cleaves interleukin 1b (IL-1b) and the pore-forming protein gasdermin D, leading to cytokine maturation and pyroptosis. NLRP3, one of the best studied inflammasomes, and pyrin are associated with many human diseases; yet where they are formed and how they are regulated and trafficked remain unknown. In this study, we found that both the NLRP3 and pyrin inflammasomes are assembled at the microtubule-organizing center (MTOC), and that interventions disrupting microtubule-mediated transport compromise the inflammasome activity. In particular, the adaptor HDAC6 for microtubule retrograde transport is important for this process in vitro and in vivo. These new understandings provide opportunities to modulate NLRP3 and pyrin signaling for potential therapeutic intervention.

What are the next steps for this research?

To address what proteins and in what forms are being directly recognized and transported by the microtuble-HDAC6 system, and how the process regulates autophagic degradation of inflammasomes.

This work was funded by:

NIH R01 Al124491, DP1 HD087988

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