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Ubiquitin, is a small protein that serves as a marker for proteasomal degradation, as well as function altering post-translational modification of substrate proteins. Ubiquitin conjugation to substrate proteins, also called ubiquitylation, is carried out by sequential action of three enzymes E1, E2 and E3, which together with the proteasome form the core of the ubiquitin-proteasome system (UPS). E3s act as specificity modules by recruiting protein substrates for ubiquitylation. E3s regulate multitudes of cellular processes by ensuring timely and accurate protein removal when the proteins are no longer needed or when their function and/or structure have been compromised. Given this role, targeting component of the UPS has been an area of intense interest in drug discovery and development. These efforts have resulted in clinically successful cancer drugs, like IMiDs, indisulam, disulfiram and bortezomib that target UPS and associated components, and have motivated us to further investigate UPS as a rational drug discovery platform.

Our current research program aims to understand how UPS regulates fate of membrane proteins, a currently poorly understood topic. In particular, we study non-transmembrane E3s targeted to membranes to facilitate ubiquitination of organellar proteins. We aim to uncover the relevance of membrane-associated degradation pathways to disease (cancer and other disease). Two areas of interest currently pursued are:

Systematic functional characterization of membrane bound E3 ubiquitin ligases:

Cellular membranes not only compartmentalize intracellular processes, but also serve as dynamic hubs for the assembly of many multi-protein complexes containing bona-fide oncoproteins, such as Ras and Receptor Tyrosine Kinases. The protein complement of cellular membranes constantly changes in response to external and internal cues. To date, very little research has addressed the role of non-transmembrane E3s in the proteolysis of membrane-bound proteins. We employ systematic approaches to investigate the regulation of membrane protein abundance by E3s/UPS. We are uncovering ubiquitin pathways that function at cellular membranes, and their underlying molecular mechanism involved in cancer and other diseases. For example, we are investigating FBXL2, an E3 ligase complex that regulates critical signaling networks operating from membrane compartments.

Systematic functional characterization of PTMs involved in regulation of membrane bound E3 ubiquitin ligases:

Often substrate degradation via ubiquitin ligases is regulated for precision and fine control. Post-translational modifications (PTMs) in response to external cues, in part, achieve this goal. Although, PTMs on substrates are well studied, PTMs on E3 ligases and how they regulate the UPS are understudied. Our work identified a novel mammalian prenyltransferase which we named GGtase3 that modifies FBXL2, an E3 ligase subunit, with geranylgeranylation (a 20-carbon lipid PTM) for localization to membrane compartments. We are currently involved in functional characterization of GGtase3 and extending our studies for functional characterization of PTMs involving membrane bound E3 ubiquitin ligases. We seek to elucidate the spatiotemporal mechanistic understating for the specificity of the ubiquitylation reaction by E3 ubiquitin ligases.

Recently described cell fitness mechanisms:

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Palmitoylation and PDE6δ Regulate Membrane-compartment Specific Substrate Ubiquitylation and Degradation

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