Lysosomes degrade extra- and intracellular macromolecules produced by endocytosis, phagocytosis, or autophagy and recycle the resulting catabolites for reutilization in cellular metabolism. They also serve as signaling hubs for integrating nutritional, energy and growth factor information and relay it to key regulatory modules. 

Lysosomes play a crucial role in cell homeostasis by acting as centers of digestion, recycling and signaling. However, very little is known about how they contribute to tissue homeostasis during development. 

Recently, Dr. WANG Xiaochen’s lab at the Institute of Biophysics of the Chinese Academy of Sciences used the nematode C. elegans for investigating lysosome function and regulation during development. They described and analyzed an interesting lysosomal morphological change in the worm epidermis during development. 

Their study, published in Developmental Cell, revealed communication between lysosomes in the cell and the extracellular matrix (ECM) structure-cuticle. 

C. elegans develops through four larval stages (L1-L4) separated by molts. During each molt, worms synthesize and secrete a new exoskeleton (“cuticle”) underneath the existing one, followed by the separation of the two exoskeletons (apolysis) and the shedding of the old one (ecdysis). Thus, the apical ECM is remodeled during molting. 

The researchers found that worms at each molting stage have extensive tubular lysosomes in the epidermis, whereas vesicular lysosomes are predominant when the worms finished molt. Also, they found that lysosome number and lysosome dynamics increased, and lysosome acidification/maturation accelerated during molting. Consistent with this, greatly increased lysosomal degradation activity was also observed in molting worms. 

In addition, the researchers investigated the mechanism behind this process. Apolysis is achieved by disruption of the attachments (FOs, Fibrous Orgenelle) between epidermis and cuticle, which must be remodeled during molting. 

They found that during molting, apical ceHD MUP-4 is downregulated, and the relative position of cuticle and epidermis is altered. They also observed lysosomal properties similar to those in molting worms when the epidermal structure was damaged upon inactivation of FO components during the intermolting stage. This suggests that epidermal structural change during molting is the upstream signal that induces lysosome activation. 

Furthermore, the researchers showed that transcription of lysosome V-ATPase genes are upregulated upon epidermal structural change when molting or when FOs are disrupted. V-ATPase is the proton pump that acidifies lysosomes. Thus, upregulation of V-ATPase gene expressions mediates lysosome activation during molting. Transcription factors STAT/STA-2 and GATA/ELT-3 are both required for the upregulation of V-ATPase genes in this process. 

This study began with an interesting observation during routine work, according to the researchers. A graduate student found lysosomes in epidermis change the pattern from vesicular shape to tubular ones during molting. Molting stage is when worms stop eating and start sleeping-lethargus. Searching for mechanism underlying reveals a cross-tissue regulation of lysosome activities. Interesting questions are remained to explore, such as cuticle collagen recycle via lysosomes in epidermis. And ECM remodeling during worm molting is similar to the process where metastatic tumor cells invade ECM. Further investigation in the communication between ECM and lysosome would help understand tumor metastasis. 

ECM remodeling and regulation of lysosome during C. elegans molting. (Image by Dr. WANG Xiaochen's group)