Membrane Trafficking Lab

THE LAB

Welcome to our lab website!

Our Lab's primary research interest is to understand the regulation of copper transporters in mammalian cell. Copper Transporter 1, CTR1 is a channel which imports copper into the cell. ATP7A and ATP7B are the ATPases (pumps) which provide copper into the secretory pathway and also help to export excess copper out of the cells. Copper is an essential micro-nutrient, serves as co-factor in various metabolic pathways. But excess copper is toxic and detrimental to biological system as it heavily participates in redox reactions generating high amount of ROS. So, the amount of copper is tightly regulated inside a cell where CTR1 and ATP7A/B participates in maintaining intracellular copper homeostasis.

We mainly focus on the trafficking regulation of these copper transporters by using high resolution imaging technique along with molecular tools to address our questions. Beside these we also study the regulation of these transporters at molecular level using MD simulation. We are also trying to develop new imaging techniques and analysis programs.

Since our major focus is trafficking of copper transporters we call ourselves as 'TRAFFICKERS'.

We are also trying to tweak the copper metabolism pathway to combat platinum drug resistance in cancer. We collaborate with IISERK Chemistry group to develop better metal-based anticancer drugs. Additionally, we study the intricate changes in mammalian copper homeostasis pathway upon pathogen and its implication in disease fate.

Research topics

Regulation of copper importer protein CTR1

CTR1 is a high affinity copper importer channel that is present on the plasma membrane (review). It first reduces environmental Cu²⁺ to bioavailable Cu¹⁺ (J. Biol. Chem., 2022), and then transports this copper into the cytoplasm, where it is distributed via intracellular chaperones (e.g., Atox1, CCS, COX17) . This 35 kDa protein forms the functional channel pore through trimerization. At basal copper levels, it resides at the plasma membrane. However, under high copper conditions, CTR1 is endocytosed to restrict further copper entry into the cell. Recently, we discovered that this process relies on noncanonical, receptor-like regulation: copper induces CTR1 clustering, which modulates the mechanical properties of the plasma membrane to drive its own endocytosis (MBoC, 2026). Apart from copper, CTR1 has also been found to import anti-cancer drug Cisplatin inside cell. Our lab focuses on these fundamental mechanisms of CTR1 regulation, copper sensing, and membrane transport.

Regulation of homologous copper ATPase pump ATP7A and ATP7B

ATP7A and ATP7B are homologous P-type ATPase that share almost 60% sequence homology (review). They have six metal binding domains on the amino terminal that regulated their activity. At normal physiological condition, they reside on trans-Golgi network (TGN) and pump Atox1-acquired copper to the secretory pathway.... At elevated copper condition, both ATP7A and ATP7B exit TGN and trafficks to baso-lateral and apical membrane respectively to export excess copper. This differential localisation accounts for systemic copper delivery by ATP7A in gut epithelia and excess copper excretion by ATP7B in liver. Mutations in ATP7A and ATP7B can result in Menken disease, Wilson Disease resulting in systemic copper deprivation and copper accumulation respectively. In an unpolarised hepatocyte, ATP7B trafficks to the lysosome and excess copper is excreted through lysosomal exocytosis (J. Cell. Sci. 2020). We have noticed copper independent trafficking of ATP7B too (Traffic 2023). Despite of high similarity, the basis of their differential trafficking is not well understood. Besides, due to their ligand mediated trafficking, they provide an exceptional model for studying polarised trafficking (J. Cell. Sci. 2023). In our lab, we are interested in understanding Trafficking regulation of ATP7A and ATP7B as a part of basic understanding of protein trafficking.

Role of copper in host-pathogen interaction using macrophage- Leishmania system

Despite the hostile microenvironment, Leishmania is known to thrive inside the phagosomes of macrophages. Copper, being a potent antimicrobial agent, has been effective against several intracellular pathogens.... The study is aimed at revealing whether Leishmania faces copper stress during infection and if so, how do they evade such stress. The work has led to the discovery of a novel copper transporter, Cu ATPase in Leishmania that is crucial for its infectivity (J. Biol. Chem. 2022). The study also reveals an interplay between the macrophage copper ATPases (channelising copper to pathogen compartments) and the pathogenic counterpart neutralising the toxic effect by exporting the metal out. Presently, we are observing an overall perturbation of cellular and systemic copper homeostasis pathway in host upon Leishmania infection, where we tried deciphering its causes and implications (Commun Biol, 2024).

Therapeutics for Wilson Disease and anti-cancer drugs

Wilson disease is caused by genetic alterations in the ATP7B gene that result in the accumulation of copper in the liver, followed by the brain and other organs. Although copper accumulation triggers Wilson disease pathology,... the oxidative stress and redox imbalance induced by copper play major roles in progressive cellular dysfunction. Existing treatments have focused on lowering copper load in the body through chelation or inhibiting copper absorption from the gut, but do not target the downstream pathological consequences of copper overload. Consequently, neurological complications and progressive tissue injury often remain inadequately controlled. The current study endeavors to revolutionize the treatment of Wilson disease by developing advanced multifunctional drugs that reduce excess labile copper via chelation and, at the same time, normalize cellular redox state through their antioxidant properties. In other words, our approach not only involves eliminating excess copper but also regulating its downstream pathological consequences. In our lab, we are trying to develop and check the potential of various small molecules that can chelate copper, reduce the downstream effect of copper accumulation, and cross the blood-brain barrier. In an effort to establish our therapeutic paradigm, we have shown that the clinically approved drug melatonin can be used to treat Wilson’s disease because of its dual functionality (chelator/antioxidant). By combining copper modulation with antioxidant activity, this strategy protects against copper-induced oxidative damage beyond what is achievable with conventional monofunctional chelation (Redox Bio, 2026). Building on this concept, we are developing guanidinium-based copper-reactivity modulators, copper-binding antioxidant peptides, and blood-brain barrier-penetrant therapeutics to target the neurological manifestations of Wilson disease. In addition to Wilson disease, the concepts that have emerged from our research offer a new therapeutic paradigm for treating disorders associated with metal toxicity, oxidative stress, and dysfunctional intracellular metal transport.