Choreographing the motor-driven endosomal dance

Abstract

The endosomal system orchestrates the transport of lipids, proteins and nutrients across the entire cell. Along their journey, endosomes mature, change shape via fusion and fission, and communicate with other organelles. This intriguing endosomal choreography, which includes bidirectional and stop-and-go motions, is coordinated by the microtubule-based motor proteins dynein and kinesin. These motors bridge various endosomal subtypes to the microtubule tracks thanks to their cargo-binding domain interacting with endosome-associated proteins, and their motor domain interacting with microtubules and associated proteins. Together, these interactions determine the mobility of different endosomal structures. In this Review, we provide a comprehensive overview of the factors regulating the different interactions to tune the fascinating dance of endosomes along microtubules.

Keywords: Dynactin; Dynein; Endoplasmic reticulum; Endosomes; Kinesin; Membrane contact sites; Microtubules.

Fig. 1.

Small GTPases, PIPs and effector proteins at the endosomal membrane recruit dynein and kinesin motors. (A) Overview of the endosomal system. Early endosomes (EE), sorting endosomes (SE), recycling endosomes (RE), late endosomes (LE), lysosomes (Lys) and autophagosomes are shown. Each compartmental membrane is marked with a unique set of GTPases (green circles with indicated Rab number) and PIPs (yellow) that recruit kinesin (light blue) and/or dynein motors (dark blue). (B,C) Schematics of kinesin-1, kinesin-2 and kinesin-3 complexes (B) and dynein–dynactin (C). Cofactors and domains of the motor heavy chains are indicated. (D–H) Schematics of the GTPases (green), PIPs (yellow), effector proteins (brown) and motor proteins (light and dark blue) recruited to distinct endosomal membranes. (D) Motor proteins are recruited to the EE membrane through interactions with the small GTPases Rab4 and Rab5, and PI(3)P. (E) Motor proteins are recruited to Rab7⁺ LEs through interactions with the small GTPase Rab7 and PI(3)P. (F) Motor proteins are recruited to Arl8b⁺ LEs through interactions with the small GTPase Arl8b. (G) Tubulation at the SE membrane requires motor protein recruitment through the small GTPases Rab10, Rab11 and Rab22a, and PI(3)P. Rab10 and Rab11 recruit KIF13A monomers, whereas Rab22a dimerizes and activates KIF13A. (H) Tubulation at the Lys membrane requires motor protein (light and dark blue) recruitment through the small GTPases Rab35 and Rab10, and PI(3,5)P₂. The kinase LRRK2 phosphorylates Rab35 and Rab10 followed by JIP4 binding to Rab10. JIP4 can interact with both dynein and kinesin, which is controlled by Arf6. PI(3,5)P₂ stimulates Ca²⁺ release through the TRPML1 Ca²⁺ channel, thereby activating the Ca²⁺ sensor ALG2 which recruits dynein. MT, microtubule.

Fig. 2.

Three models for bidirectional endosomal movement. (A) In the recruitment model, dynein and kinesin motors alternate their recruitment to the endosomal membrane. Directionality is determined by the type of motor bound at a defined moment in time. (B) In the coordination model, both dynein and kinesin motors are associated with the endosome, but only one type of motor is active at a given time. (C) In the tug-of-war model, both motors are actively bound to the endosome, providing force in opposite directions. The team of motors generating the greatest force wins and determines the direction of movement. Kinesin-1 is shown as an example kinesin; PN, perinuclear; PP, periphery.

Fig. 3.

MAPs and tubulin-PTMs affect motor binding to the microtubule. (A) Selection of MAPs and their inhibiting (orange lines) or stimulating (green lines) effects on dynein, kinesin-1, kinesin-2 and kinesin-3 motility. (B) PTMs that can be present on the α- and β-tubulin subunits of the microtubule.

Fig. 4.

Proteins at ER–LE contact sites regulate endosomal positioning and transport. (A) Schematic overview of endosomal localization inside the cell, including the perinuclear endosomal cloud and the peripheral endosomes connected to the ER. (B) The ER-resident proteins RNF26 (an E3 ligase) and UBE2J1 (an E2 enzyme) recruit and ubiquitylate SQSTM1, which in turn binds the ubiquitin-binding endosomal proteins TOLLIP (LE/Lys) or EPS15 (EEs), linking endosomes to the ER membrane. UBD, ubiquitin-binding-domain; Ub, ubiquitin. (C) Left, the ER-embedded protein protrudin interacts with Rab7 and PI(3)P at the endosomal membrane and with VAPA at the ER membrane. Protrudin facilitates loading of kinesin-1 onto FYCO1–Rab7 at the endosomal membrane, promoting anterograde endosomal transport. Right, during starvation, kinesin-mediated transport is inhibited by low PI(3)P levels when FYCO1 and protrudin dissociate from the endosomal membrane. Malonyl-CoA synthesis is also inhibited, resulting in CPT1C that is not bound to malonyl-CoA, which prevents protrudin from transferring kinesin-1 to FYCO1. (D) Cholesterol (high) at the endosomal membrane interacts with the ORD domain of ORP1L, allowing dynein to interact with the RILP–Rab7 complex inducing retrograde endosomal transport. When endosomal cholesterol levels decrease (low), the ORP1L FFAT domain interacts with the ER-resident protein VAPA, leading to dissociation of dynein.