Research Project 6:
Lysosomal chloride and membrane traffic of and to lysosomes
The ubiquitously expressed Cl-/H+ exchanger ClC-7 localizes with its β-subunit Ostm1 to lysosomes and to the ruffled border of osteoclasts. Dysfunction of ClC-7/Ostm1 leads to osteopetrosis and a lysosomal storage disease with neurodegeneration in humans and mice. The osteopetrosis might be due to an underdevelopment of the ruffled border of osteoclasts, which is normally formed by massive lysosomal exocytosis, and an impaired acidification of the resorption lacuna. The lysosomal pathology involves a slowed degradation of endocytosed protein in renal proximal tubules and an alteration of lysosomal morphology in various tissues. In contrast to the acidification of the resorption lacuna, acidification of lysosomes is unaffected by the loss of ClC-7/Ostm1. The physiological role of ClC-7/Ostm1 requires the pH gradient-driven luminal accumulation of chloride mediated through its Cl-/H+ exchange activity, but it remains unknown how this affects lysosomal morphology and function.
In this project, we use a broad range of methods (biophysics, molecular biology, live-cell microscopy and mouse models) to study how altered chloride transport impinges on the morphology of lysosomes, on various vesicular trafficking steps in the degradative pathway and on signaling from lysosomes.
Weinert S, Jabs S, Hohensee S, Chan WL, Kornak U, Jentsch TJ (2014) Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions. EMBO Rep 15: 784-91
Stauber T, Jentsch TJ (2013) Chloride in vesicular trafficking and function. Annu Rev Physiol 75: 453-77
Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T (2011) ClC-7 is a slowly voltage-gated 2Cl–/1H+-exchanger and requires Ostm1 for transport activity. EMBO J 30: 2140-52
Weinert S, Jabs S, Supanchart C, Schweizer M, Gimber N, Richter M, Rademann J, Stauber T, Kornak U, Jentsch TJ (2010) Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl– accumulation. Science 328: 1401-3
Wartosch L, Fuhrmann JC, Schweizer M, Stauber T, Jentsch TJ (2009) Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7. FASEB J 23: 4056-68
Kasper D, Planells-Cases R, Fuhrmann JC, Scheel O, Zeitz O, Ruether K, Schmitt A, Poët M, Steinfeld R, Schweizer M, Kornak U, Jentsch TJ (2005) Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J 24: 1079-91