Microtubule motors transport phagosomes in the RPE, and lack of KLC1 leads to AMD-like pathogenesis.
The degradation of phagosomes, derived from the ingestion of photoreceptor outer segment (POS) disk membranes, is a major role of the retinal pigment epithelium (RPE). Here, POS phagosomes were observed to associate with myosin-7a, and then kinesin-1, as they moved from the apical region of the RPE. Live-cell imaging showed that the phagosomes moved bidirectionally along microtubules in RPE cells, with kinesin-1 light chain 1 (KLC1) remaining associated in both directions and during pauses. Lack of KLC1 did not inhibit phagosome speed, but run length was decreased, and phagosome localization and degradation were impaired. In old mice, lack of KLC1 resulted in RPE pathogenesis that was strikingly comparable to aspects of age-related macular degeneration (AMD), with an excessive accumulation of RPE and sub-RPE deposits, as well as oxidative and inflammatory stress responses. These results elucidate mechanisms of POS phagosome transport in relation to degradation, and demonstrate that defective microtubule motor transport in the RPE leads to phenotypes associated with AMD.
Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90095.
Mei
M
Jiang
Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90095.
Julian
J
Esteve-Rudd
Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90095 Centre of Ophthalmology, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University Coimbra, 3000-548 Coimbra, Portugal.
Vanda S
VS
Lopes
Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90095.
Tanja
T
Diemer
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Concepción
C
Lillo
Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90095.
Agrani
A
Rump
Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA 90095 Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095 Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093 dswilliams@ucla.edu.
David S
DS
Williams
D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D003167:Complement Activation; D016547:Kinesins; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D018384:Oxidative Stress; D010588:Phagosomes / Q000378:metabolism*; D055214:Retinal Photoreceptor Cell Outer Segment / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism*
C000715695:Kns2 protein, mouse; D008869:Microtubule-Associated Proteins; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009218:Myosins; D016547:Kinesins