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Strict control over degradation of individual proteins at the correct time and space in cells is key for dynamic transitions in cell signaling. Protein modification by the modifier ubiquitin is recognized as a fundamental mechanism to target proteins to the main protease complex in the cell: the proteasome. Cell-free and structural studies have provided mechanistic insight into how ubiquitinated proteins are recognized and degraded by the proteasome. However, many principles and regulators of how ubiquitination, proteasome targeting, target extraction from sub-cellular sites, and fate-determinations at the proteasome in the crowded intracellular space are achieved, remain unknown.
Main questions addressed are: 1) How are immune- and cancer-associated proteins targeted to the proteasome, 2) which other cellular factors control their degradation, 3) are these processes deregulated in cancer and immune disease, and 4) how do they mechanistically determine cellular protein fate decisions?
To identify novel cellular regulators of proteasome-dependent degradation, the Versteeg lab utilizes genome-wide genetic screening approaches. There is a strong focus on the discovery of factors controlling the degradation of disease-associated proteins with different conceptual properties, such as ubiquitin-independent, and activation-coupled proteasomal degradation. Following identification of key players in protein stability, we aim to determine the molecular mechanisms by which these regulators control degradation of their targets using cell-biology approaches, and biochemical in vitro reconstitution.
Gijs Versteeg studied Biomedical Sciences, and obtained his PhD in Molecular Virology at the University of Leiden, The Netherlands. He further continued his research on cellular immune signaling responses as a post-doctoral fellow in the Influenza Center of Excellence at Mount Sinai School of Medicine in New York City. Gijs started his independent research group at the Max Perutz Labs in 2013.
Most cellular proteins are present in the majority of mammals, and are essential for life. Yet, few of them are only found in humans, and often have non-essential functions. We recently discovered that a human-specific –non-conserved– RING protein is essential for cancer cells. Its genetic deletion de-represses a cellular stress response, thereby bringing a stop to cell division.
Unstructured regions with a diverse amino acid composition in proteins are key for initiating proteasomal degradation. Consequently, repetitive sequences are poor degradation-initiation sites. We recently discovered one of the most unstable proteins in human cells with a three-minute half-life. Unexpectedly, its extreme instability is dependent on a large, repetitive protein loop.
Membranes are sites of intense signaling activity in eukaryotic cells. Essential processes...
Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response.
Rajsbaum, Ricardo; Versteeg, Gijs A; Schmid, Sonja; Maestre, Ana M; Belicha-Villanueva, Alan; Martínez-Romero, Carles; Patel, Jenish R; Morrison, Juliet; Pisanelli, Giuseppe; Miorin, Lisa; Laurent-Rolle, Maudry; Moulton, Hong M; Stein, David A; Fernandez-Sesma, Ana; tenOever, Benjamin R; García-Sastre, Adolfo
The E3-ligase TRIM family of proteins regulates signaling pathways triggered by innate immune pattern-recognition receptors.
Versteeg, Gijs A; Rajsbaum, Ricardo; Sánchez-Aparicio, Maria Teresa; Maestre, Ana M; Valdiviezo, Julio; Shi, Mude; Inn, Kyung-Soo; Fernandez-Sesma, Ana; Jung, Jae; García-Sastre, Adolfo
Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor.
Mata, Miguel A; Satterly, Neal; Versteeg, Gijs A; Frantz, Doug; Wei, Shuguang; Williams, Noelle; Schmolke, Mirco; Peña-Llopis, Samuel; Brugarolas, James; Forst, Christian V; White, Michael A; García-Sastre, Adolfo; Roth, Michael G; Fontoura, Beatriz M A
Project title: "Inhibition of macrophage activation by TRIM47"
The Versteeg group is associated with the Vienna Doctoral School: PhD track Signaling Mechanisms in Cellular Homeastasis.
Project title: "Inhibition of the antiviral immune response by TRIM52"