Author ORCID Identifier
0000-0003-0443-9371
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human Genetics
First Advisor
Senthil Radhakrishnan
Abstract
Proteasome inhibitors are FDA-approved therapies for multiple myeloma and mantle cell lymphoma; however, their clinical efficacy is limited by the emergence of adaptive resistance mechanisms. A major contributor to this resistance is the activation of compensatory proteostasis pathways in response to proteotoxic stress. The ubiquitin–proteasome system (UPS) and autophagy are two interconnected quality control mechanisms that maintain protein homeostasis, so that disruption of proteasome function often triggers compensatory autophagy.
Here, we define two complementary mechanisms linking proteasome dysfunction to autophagy activation. First, we reveal a post-transcriptional proteostasis mechanism involving DNA damage–inducible 1 homolog 2 (DDI2). DDI2 deficiency resembled proteasome dysfunction, leading to intracellular accumulation of Cellular Communication Network 1 (CCN1) without altering its transcription which induced compensatory autophagy. We demonstrate that intracellular, misfolded CCN1 is sufficient to trigger autophagy through reactive oxygen species–dependent signaling. Mechanistically, CCN1 is processed through endoplasmic reticulum quality control pathways involving p97/VCP and transferred to lysosomes by DDI2. Loss of DDI2 impaired CCN1 delivery to lysosomes, suggesting a role for DDI2 in selective autophagic targeting. Second, we identified secretory protein CCN1 as a stress-responsive transcriptional target of NRF1 during proteasome inhibition. Loss of NRF1 significantly reduced CCN1 transcription and protein expression following carfilzomib treatment, while overexpressed NRF1 increased CCN1 levels. Genetic ablation of CCN1 impaired autophagy in response to proteasome inhibition, whereas CCN1 overexpression restored reduced autophagy in NRF1-deficient cells, establishing CCN1 as a key downstream mediator of NRF1 -dependent autophagy.
Together, these findings establish CCN1 as a central integrator of proteasome stress and autophagy and reveal distinct transcriptional and post-transcriptional mechanisms through which NRF1 and DDI2 coordinate adaptive proteostasis, respectively. This study provides new insights into potential strategies to overcome resistance to proteasome inhibitor–based cancer therapies.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-11-2026