A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair.
Lysosome exocytosis plays a major role in resealing plasma membrane (PM) disruptions. This process involves two sequential steps. First, lysosomes are recruited to the periphery of the cell and then fuse with the damaged PM. However, the trafficking molecular machinery involved in lysosome exocytosis and PM repair (PMR) is poorly understood. We performed a systematic screen of the human Rab family to identify Rabs required for lysosome exocytosis and PMR. Rab3a, which partially localizes to peripheral lysosomes, was one of the most robust hits. Silencing of Rab3a or its effector, synaptotagmin-like protein 4a (Slp4-a), leads to the collapse of lysosomes to the perinuclear region and inhibition of PMR. Importantly, we have also identified a new Rab3 effector, nonmuscle myosin heavy chain IIA, as part of the complex formed by Rab3a and Slp4-a that is responsible for lysosome positioning at the cell periphery and lysosome exocytosis.
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
Marisa
M
Encarnação
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
Lília
0000-0002-6218-7785
L
Espada
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
Cristina
0000-0002-2183-3947
C
Escrevente
Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Denisa
D
Mateus
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
José
0000-0002-1927-164X
J
Ramalho
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Xavier
X
Michelet
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
Inês
I
Santarino
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Victor W
VW
Hsu
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Michael B
MB
Brenner
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
Duarte C
0000-0001-8867-2407
DC
Barral
Centro de Estudos de Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal otilia.vieira@nms.unl.pt.
Otília V
0000-0003-4924-1780
OV
Vieira
D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear; D008247:Lysosomes / Q000378:metabolism* / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020826:rab3A GTP-Binding Protein / Q000378:metabolism*
C512779:SYTL4 protein, human; D033921:Vesicular Transport Proteins; D018995:Myosin Heavy Chains; D020826:rab3A GTP-Binding Protein