Research
Identification of lysosomes as transport vehicles for RNA granules in neuronal axons
Polarized cells, such as neurons, depend on continuous, long-distance RNA transport to maintain specialized functions such as synaptic activity. Mutations in RNA binding proteins and their associated transport machinery cause a host of neurodegenerative diseases. We found that RNA is transported over long distances within axons through the tethering of RNA granules to motile lysosomes. We identified the ALS-associated protein Annexin A11 (ANXA11) as a tethering protein that links RNA granules to lysosomes. ANXA11's unique structure allows its function as a molecular tether between RNA granules and lysosomes. Its N-terminus is dominated by a low- complexity (LC) domain that can bind to RNA granules, while its C-terminus is made up of calcium- and membrane-binding annexin repeats, which enable binding to lysosomal membranes. In rodent neurons and living zebrafish embryo axons, we found that ANXA11-mediated RNA granule-lysosome docking facilitates long-distance RNA trafficking, while ALS-associated ANXA11 mutations impair lysosome tethering functions and RNA transport.
Stress adaption by lysosomes turnover early secretory pathway unit ER exit sites
Cellular versatility depends on the accurate trafficking of diverse proteins to their destinations. ER exit sites (ERES), the first portage of the secretory pathway, are highly regulated to help cells adapt and cope with various stresses. We used whole-cell focused ion beam scanning electron microscopy (FIB-SEM) to reveal an 8 nm resolution 3D structure of ERESs and their interactions with lysosomes in cells under various stresses. We found that inhibition of mTOR, a central nutrient signaling complex, drastically increases lysosome-ERES contacts and promotes the degradation of secretory cargos residing in ERESs. ERES-lysosome membrane contacts are initiated by stress-induced lysosomal calcium release and post-translational modification of the ERES coatomer COPII complex. This membrane contact is further bridged by calcium-activated ALG2 binding to ERESs and ALG2’s binding partner ALIX recruitment to the lysosomal membrane. This process helps cells cope with nutrient deprivation stress by eliminating secretion sites, diverting the contents of the early secretory pathway for degradation, and potentially providing immediate access to amino acids for stress response protein synthesis.