title: Vps35-dependent recycling of Trem2 regulates microglial function.
abstract: Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11. When Vps35 is knocked down, Trem2 accumulated in the lysosomes but was not degraded. More importantly, Vps35 deficiency leads to excessive lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and IL-6 production, which can be abolished by Trem2 overexpression. Furthermore, R47H Trem2, an AD-associated mutant, failed to interact with Vps35 and became unstable compared with wild-type Trem2. Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as proinflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to AD.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: Qingdao Mental Health Center, Qingdao, China.
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: He
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Lujun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology / Q000502:physiology; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D033921:Vesicular Transport Proteins; C101274:Vps35 protein, mouse; C577686:interleukin-6, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Alzheimer's disease; Trem2; Vps35; microglia; receptor recycling; retromer