Lysosomes at the nexus of cellular quality control and metabolism

Lysosomes sit at the crossroads of cellular catabolism and quality control, where they must dismantle chemically diverse cargo while preserving their own integrity. I will discuss two discoveries that reveal how lysosomes solve these complementary challenges and how their failure creates disease vulnerabilities. First, I will describe Lysosomal Leucine Aminopeptidase (LyLAP), an enzyme specialized to processively degrade the hydrophobic α-helices of transmembrane proteins. LyLAP is highly expressed in pancreatic ductal adenocarcinoma, where its loss causes hydrophobic peptides to accumulate, compromises lysosomal function, and ultimately leads to cancer cell death, revealing a potential vulnerability in tumors with elevated endocytic activity. I will then describe LASER, a damage-responsive protein assembly that couples lysosomal membrane injury to repair. At its core, the oligomeric protein TFG recognizes LC3/GABARAP proteins conjugated to damaged lysosomes and recruits the ESCRT machinery to restore membrane integrity. Neurodegenerative disease-associated mutations in TFG disrupt this process, linking defective lysosomal repair to human disease. Together, these findings reveal lysosomes as dynamic systems that coordinate cargo degradation with membrane surveillance and repair to maintain cellular homeostasis. 

More about Dr. Aakriti Jain's lab at UTSW: https://aakritijainlab.com/