Tau differentially regulates the transport of early endosomes and lysosomes

Abstract

Microtubule-associated proteins (MAPs) modulate the motility of kinesin and dynein along microtubules to control the transport of vesicles and organelles. The neuronal MAP tau inhibits kinesin-dependent transport. Phosphorylation of tau at tyrosine 18 by fyn kinase results in weakened inhibition of kinesin-1. We examined the motility of early endosomes and lysosomes in cells expressing wild-type (WT) tau and phosphomimetic Y18E tau. We quantified the effects on motility as a function of the tau expression level. Lysosome motility is strongly inhibited by tau. Y18E tau preferentially inhibits lysosomes in the cell periphery, while centrally located lysosomes are less affected. Early endosomes are more sensitive to tau than lysosomes, and are inhibited by both WT and Y18E tau. Our results show that different cargoes have disparate responses to tau, likely governed by the types of kinesin motors driving their transport. In support of this model, kinesin-1 and -3 are strongly inhibited by tau while kinesin-2 and dynein are less affected. In contrast to kinesin-1, we find that kinesin-3 is strongly inhibited by phosphorylated tau. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

Choreographing the motor-driven endosomal dance

“…1 D–F). This difference might be the result of a phosphorylated form of tau that inhibits kinesin-3 function, but not kinesin-1, even more strongly than the non-phosphorylated form ( Balabanian et al, 202 2). By inhibiting kinesin motors, tau favors retrograde endosomal movement ( Chaudhary et al, 2018 ).…”

Tau oligomerization on microtubules in health and disease

“…Several studies have shown that tau is a general inhibitor of motor transport, reducing the landing rate for all transport motors: kinesin‐1, kinesin‐2, kinesin‐3, and the processive dynein‐dynactin complex (Balabanian et al, 2022; Chaudhary et al, 2018; Dixit et al, 2008; Ebneth et al, 1998; Monroy et al, 2018; Monroy et al, 2020; Tan et al, 2019; Figure 1a). The effects on kinesin motors are more pronounced than on the dynein motor, due in part to the overlapping binding sites of tau and kinesin motor domains on the microtubule lattice (Tan et al, 2019).…”

It takes tau to tango: Investigating the fuzzy interaction between the R2-repeat domain and tubulin C-terminal tails

“…16 It regulates the MTs assembly and spatial organization, 17 and controls the motility of motor proteins on MTs. [18][19][20][21] Tau is involved in numerous neurodegenerative diseases, named tauopathies, including Alzheimer's disease (AD), which are characterized by fibrillar aggregation. 22 The binding of tau on MTs, and its propensity to aggregate are affected by PTMs, in particular the hyperphosphorylation of tau has been shown to be involved in several pathologies.…”