A septin GTPase scaffold of dynein–dynactin motors triggers retrograde lysosome transport

Abstract

The metabolic and signaling functions of lysosomes depend on their intracellular positioning and trafficking, but the underlying mechanisms are little understood. Here, we have discovered a novel septin GTPase–based mechanism for retrograde lysosome transport. We found that septin 9 (SEPT9) associates with lysosomes, promoting the perinuclear localization of lysosomes in a Rab7-independent manner. SEPT9 targeting to mitochondria and peroxisomes is sufficient to recruit dynein and cause perinuclear clustering. We show that SEPT9 interacts with both dynein and dynactin through its GTPase domain and N-terminal extension, respectively. Strikingly, SEPT9 associates preferentially with the dynein intermediate chain (DIC) in its GDP-bound state, which favors dimerization and assembly into septin multimers. In response to oxidative cell stress induced by arsenite, SEPT9 localization to lysosomes is enhanced, promoting the perinuclear clustering of lysosomes. We posit that septins function as GDP-activated scaffolds for the cooperative assembly of dynein–dynactin, providing an alternative mechanism of retrograde lysosome transport at steady state and during cellular adaptation to stress.

Neuronal-specific septin-3 binds Atg8/LC3B, accumulates and localizes to autophagosomes during induced autophagy

“…(ii) Nevertheless, LIR motifs can be found in autophagy-related, but non autophagy-receptor proteins that play role in autophagosome transport or maturation [ 33 ]. A recent study revealed that another septin from the SEPT3 subgroup, septin-9 acts as an adaptor protein by recruiting dynein-dynactin to lysosomes and enhances their retrograde transport during stress [ 82 ]. Septin-9 also binds a kinesin [ 83 ].…”

The axonal endolysosomal and autophagic systems

“…Interestingly, a local disruption of microtubules and the axonal actin-spectrin cytoskeleton, phenotypes that are accompanied by an increase in total and phosphorylated tau protein, have been recently found in JIP3 KO iPSC-derived cortical glutamatergic neurons, phenotypes that are further aggravated by the co-depletion of its paralog JIP4 (Rafiq et al 2020). A tight link between the retrograde dynein-driven transport of lysosomes and the cytoskeletal scaffold protein Septin-9 has been reported in non-neuronal cells (Kesisova et al 2020). Future studies are thus needed to define the exact roles of the various forms of the axonal cytoskeleton in the anterograde and retrograde movement of (pre)lysosomes and autophagosomes.…”

“…A tight link between the retrograde dynein‐driven transport of lysosomes and the cytoskeletal scaffold protein Septin‐9 has been reported in non‐neuronal cells (Kesisova et al . 2020). Future studies are thus needed to define the exact roles of the various forms of the axonal cytoskeleton in the anterograde and retrograde movement of (pre)lysosomes and autophagosomes.…”

Cytoskeleton and Associated Proteins: Pleiotropic JNK Substrates and Regulators

“…In addition, a link between septins and JNK may exist in the environment of MTs. Indeed, septins are scaffold partners of MAPs on MTs, including the structural MAP4, the tubulin-deacetylase HDAC6 (for review [180]), the dynein/dynactin motor complex [181] and maybe the +TIPs CLIP-170 and MCAK [158]. Also, SEPT9 mediates a dyneindependent retrograde transport of lysosomes, and this property is enhanced upon arsenite stress, a well-known JNK activator.…”