Abstract
Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network.
Highlights
Valosin-containing protein (VCP), the homologue of yeast Cdc48, is the causative gene for a multisystem degenerative disease that was originally termed IBMPFD to encompass the wide range of debilitating clinical outcomes, including inclusion body myopathy (IBM), Paget’s disease of the bone (PDB) and frontotemporal dementia (FD) (Watts et al, 2004)
We demonstrate that lysosomes form a dynamic, tubular array that extends throughout the sarcoplasm of Drosophila muscle, in vivo. This is the first observation of such an extensive, dynamic tubular lysosomal network in any in vivo system
We define this as a lysosomal network because it has a low pH, it is labeled by the late endosomal marker Spin-GFP, does not colocalize with the ER, golgi apparatus, early endosomes or recycling endosomes, and we find that mCherry-Atg8 traffics to this compartment, indicative of autophagosome fusion with a network of tubular lysosomes
Summary
Valosin-containing protein (VCP), the homologue of yeast Cdc, is the causative gene for a multisystem degenerative disease that was originally termed IBMPFD to encompass the wide range of debilitating clinical outcomes, including inclusion body myopathy (IBM), Paget’s disease of the bone (PDB) and frontotemporal dementia (FD) (Watts et al, 2004). Muscle biopsies from patients with VCP-related diseases display an accumulation of cytoplasmic poly-ubiquitin aggregates (Watts et al, 2004; Weihl et al, 2009; Dolan et al, 2011), suggesting a major defect in protein clearance. Over-expression of VCP mutant transgenes with disease causing mutations leads to an accumulation of autophagosomes (Ju et al, 2009; Tresse et al, 2010a), suggesting that VCP functions in processes related to the maturation or fusion of autophagosomes with lysosomes
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