Research in the Strieter lab seeks to understand how ubiquitin-dependent signaling directs proteasomal degradation and maintains protein homeostasis. A central focus of our work is defining how the nature of a ubiquitin modification—and the properties of the modified substrate—govern recognition, processing, and degradation by the proteasome.
Addressing these questions often requires a detailed examination of proteasomal subunits themselves, with particular emphasis on their specificities and responses to distinct ubiquitin architectures and modified proteins. Our research integrates chemical biology, biochemistry, structural approaches, cell biology, and mass spectrometry to dissect the mechanisms that control protein fate and function.
Ubiquitin Chain Architecture and Proteasomal Degradation
Ubiquitin chains are structurally diverse, and this diversity plays a critical role in determining substrate fate. Our laboratory has a long-standing interest in how branched and mixed-linkage ubiquitin chains are recognized and processed by the proteasome.
We have identified and characterized mechanisms by which proteasome-associated deubiquitinases selectively recognize and remodel specific ubiquitin architectures. In particular, we study how these enzymes edit ubiquitin chains to promote or restrict substrate degradation. This work has uncovered principles by which chain topology, rather than simply chain length, can dictate proteasomal outcomes.
Chemical Biology Tools to Probe Ubiquitin Biology
A major emphasis of the lab is the development of chemical and protein-based tools to interrogate ubiquitin signaling pathways. These include:
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Synthetic ubiquitin conjugates with defined architectures
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Activity-based probes and engineered inhibitors for deubiquitinases
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Nanobody-based modulators that enable selective perturbation of proteasome-associated enzymes
These tools allow us to move beyond descriptive studies and directly test mechanistic hypotheses in complex biochemical systems and cellular models.
Integrative Mass Spectrometry Approaches
To connect molecular mechanism with function, we use a combination of mass spectrometry-based methods along with computational modeling to map ubiquitin chain topology and protein–protein interactions at high resolution. These approaches enable us to characterize ubiquitin modifications that are difficult or impossible to resolve using conventional methods and to directly link structural features to enzymatic activity.
Proteostasis and Neural Function
An emerging direction in the lab focuses on the role of ubiquitin-dependent proteostasis in neuronal signaling and synaptic plasticity. We are particularly interested in how regulated protein degradation contributes to learning, memory, and neurodevelopment, and how defects in these pathways lead to neurological disease. By combining biochemical reconstitution with cellular and neuronal models, we aim to define how ubiquitin signaling pathways operate in physiologically relevant contexts.
Training and Interdisciplinary Research
Our research program is highly interdisciplinary, and lab members are trained to think across traditional boundaries. Trainees develop expertise in chemical synthesis, protein biochemistry, cell culture, fluorescence imaging and cell-sorting techniques, and mass spectrometry, while learning to frame mechanistic questions that bridge chemistry and biology.