How Lis1 Switches Dynein Motors to Control Cellular Transport
Research Summary: Lis1 is a key regulator of cytoplasmic dynein, a microtubule motor responsible for retrograde transport in cells. We reveal how Lis1 switches dynein between inactive and active states through two regulators, COP9 Signalosome (CSN) and PRMT5, uncovering a molecular mechanism that fine-tunes intracellular transport.
Researcher Spotlight
Devanshi Gupta is a research scholar in the laboratory of Dr. Maddika Subba Reddy at BRIC–Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad. She completed her MSc in Biotechnology from Banaras Hindu University (BHU), Varanasi. During her doctoral research, she focused on uncovering novel functional roles of LisH-domain–containing proteins, including the identification of modification-dependent regulatory switches controlling the Lis1–dynein axis. She has recently defended her PhD and is ready to move on to her next phase to understand new and exciting questions in science.
Linkedin: www.linkedin.com/in/guptadevanshi/
Twitter: https://x.com/DevanshiGup
Instagram: www.instagram.com/agirlinwhitecotton/
Lab: Dr Maddika Subbareddy, BRIC – Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad
LinkedIn: www.linkedin.com/company/bric-cdfd/
Twitter: https://x.com/BRIC_CDFD
Instagram: www.instagram.com/bric_cdfd/
What was the core problem you aimed to solve with this research?
Lis1 is known to both inhibit and activate dynein, but how it switches between these opposite roles was unclear. We unveiled the first mechanistic explanation behind these contrasting functions and understand how its failure contributes to the neurodevelopmental disorder, lissencephaly.
How did you go about solving this problem?
We systematically analyzed Lis1’s protein interaction network and identified CSN and PRMT5 as previously unrecognized partners. We then used immunofluorescence and live-cell super-resolution microscopy to quantify dynein motility when these regulators were present or depleted. To define the underlying mechanism, we performed biochemical immunoprecipitation and enzymatic assays, which revealed that CSN removes a regulatory modification from dynein to inactivate it, while PRMT5 methylates Lis1, displacing CSN and enabling dynein activation. Together, these approaches allowed us to connect molecular interactions with functional transport outcomes in cells.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Much like road traffic, cells rely on a tightly regulated transport system to move essential cargo to the right place at the right time. In this study, we discovered that a single protein, Lis1, acts as both a brake and an accelerator for a cellular motor called dynein. Lis1 partners with one regulator to stop dynein movement, and with another to start and move the motor. This coordinated control ensures smooth cellular transport and is especially important during early brain development.
What are the potential implications of your findings for the field and society?
Our study identifies specific regulatory steps that break down in lissencephaly, particularly faulty interactions between Lis1 and its regulators, CSN and PRMT5, which disrupt cellular transport. By pinpointing these control points, the work provides a clearer framework for understanding dynein-related neurodevelopmental disorders. Although lissencephaly is a genetic condition and direct therapies remain speculative, our findings suggest that targeting regulatory pathways controlling protein modifications may, in the long term, inform strategies to rebalance cellular transport in related neurological disorders.
How do cells keep their intracellular highways moving without traffic jams? In our recent Cell Reports study, Devanshi Gupta uncovers how a single protein, Lis1, acts as a molecular switch for the dynein motor—holding it OFF through cooperation with the CSN complex, or flipping it ON after PRMT5-mediated modification to drive directional cargo transport inside cells. — Dr Maddika Subbareddy
What was the exciting moment during your research?
One real “aha” moment came when we observed a chemical modification called neddylation on dynein, something previously linked mainly to ubiquitin pathways. That unexpected result immediately raised new questions and set the direction for the rest of the study. Another key moment was when we analyzed disease-linked Lis1 mutations and saw a clear pattern: some mutations disrupted Lis1’s interaction with one regulator while strengthening its interaction with another, leading to opposite effects on dynein movement. Together, these findings brought the entire mechanism into focus and gave us confidence that we were uncovering a coherent and meaningful regulatory system.
Paper reference: Gupta, D., & Maddika, S. (2026). COP9 signalosome and PRMT5 methylosome complexes are essential regulators of Lis1-dynein-based transport. Cell Reports, 45(1), 116736. doi: 10.1016/j.celrep.2025.116736
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