The trafficking of TMEM106B, a risk factor for neurodegeneration, is regulated by N1-Src kinase

TMEM106B (lysosomal transmembrane protein 106B) is a known genetic risk factor for frontotemporal lobar degeneration (FTLD) with TDP43 inclusions and is associated with other forms of neurodegeneration including Alzheimer’s disease. The function of TMEM106B is unknown, although overexpression of TMEM106B protein in neurons affects lysosomal acidification, morphology, localisation and lipid metabolism. More recently, the cytoplasmic N-terminus of TMEM106B was identified as a substrate for c-Src and its neuronal splice variant, N1-Src, tyrosine kinases observed to be over-active in neurodegeneration. The Src tyrosine phosphosite, Y50, is located within a putative YXXϕ motif of TMEM106B, a conserved sorting signal recognised by endocytic adaptor protein (AP) complexes to facilitate clathrin-mediated endocytosis. This study aimed to investigate how N1-Src-mediated phosphorylation of TMEM106B regulates its trafficking and lysosomal function, and potentially shed light on its role in neurodegenerative disease.