Biology Seminar - Ivan Dikic

Cellular homeostasis relies on highly coordinated quality-control systems that monitor protein integrity, organelle function, and genome stability. Among these, ubiquitin-dependent signaling and selective autophagy form an integrated network that safeguards cells against proteotoxic, metabolic, and genotoxic stress. Beyond their classical roles in protein degradation, ubiquitin pathways orchestrate diverse processes including endocytosis, translation, innate immunity, and DNA repair, thereby shaping cellular adaptation and survival.

In this lecture, I will discuss how ubiquitination and autophagy cooperate to maintain cellular integrity under conditions of stress. I will present recent insights into how defects in RNA splicing, caused by deficiency of the snRNP component USP39, trigger proteotoxic stress responses that engage selective autophagy pathways. I will also highlight mechanisms by which loss of the metalloprotease SPRTN, a key factor resolving DNA-protein crosslinks, couples genome instability to ubiquitin-driven quality control systems. In addition, I will introduce Contact-phagy, a newly identified form of selective autophagy that regulates endoplasmic reticulum contact sites with mitochondria and other organelles, thereby controlling organelle communication and metabolic homeostasis. Finally, I will discuss how mechanistic insights into ubiquitin networks are enabling new therapeutic strategies. Through the PROXIDRUGS initiative, we are developing proximity-inducing modalities, including PROTACs and molecular glues, that harness ubiquitin-dependent degradation to target disease-relevant proteins, nucleic acids, and even organelles.

Together, these studies illustrate how ubiquitin and autophagy networks function as central guardians of cellular homeostasis and how their manipulation opens new avenues for therapeutic intervention.

Host: Alexander Varshavsky