Intersectin-1 interacts with the golgin GCC88 to couple the actin network and Golgi architecture

Abstract

The maintenance of the Golgi ribbon relies on a dynamic balance between the actin and microtubule networks; however, the pathways controlling actin networks remain poorly defined. Previously, we showed that the trans-Golgi network (TGN) membrane tether/golgin, GCC88, modulates the Golgi ribbon architecture. Here, we show that dispersal of the Golgi ribbon by GCC88 is dependent on actin and the involvement of nonmuscle myosin IIA. We have identified the long isoform of intersectin-1 (ITSN-1), a guanine nucleotide exchange factor for Cdc42, as a novel Golgi component and an interaction partner of GCC88 responsible for mediating the actin-dependent dispersal of the Golgi ribbon. We show that perturbation of Golgi morphology by changes in membrane flux, mediated by silencing the retromer subunit Vps26, or in a model of neurodegeneration, induced by Tau overexpression, are also dependent on the ITSN-1-GCC88 interaction. Overall, our study reveals a role for a TGN golgin and ITSN-1 in linking to the actin cytoskeleton and regulating the balance between a compact Golgi ribbon and a dispersed Golgi, a pathway with relevance to pathophysiological conditions.

Form and function of the Golgi apparatus: scaffolds, cytoskeleton and signalling

“…As for other golgins, GCC88 is a parallel homo-dimer with 80% of the sequence predicted to be coiled-coil structures [52]. In addition to a role in regulating endosometo-TGN retrograde transport [53], GCC88 has recently been shown by our laboratory to be coupled to the actin cytoskeleton [42]. A modest overexpression of GCC88 results in disruption of the Golgi ribbon and dispersal of intact Golgi mini-stacks throughout the cytoplasm, a finding which provided a strategy to explore the function of the Golgi ribbon.…”

“…Depletion of GCC88 by siRNA in these clones restored the Golgi ribbon, with the length of the Golgi cisternae even longer than those of the parental cells . Treatment with actin depolymerising drugs resulted in a reversal of the phenotype mediated by the overexpression of GCC88 . Thus, GCC88 regulates the balance between Golgi mini‐stacks and Golgi ribbon by an actin‐dependent process.…”

“…Shown is the model proposed by Makhoul et al . for coupling the interaction between GCC88 and ITSN‐1 with actin polymerisation at the TGN. GCC88 binds and recruits the long form ITSN‐1 to the TGN.…”

Golgi Structure and Function in Health, Stress, and Diseases

“…A recent report suggests that GCC88-induces Golgi ribbon dispersal via actin and non-muscle myosin IIA. In addition, a novel GCC88-binding partner, the long isoform of intersectin-1 (ITSN-1), a guanine nucleotide exchange factor for Cdc42, is identified to be involved in this process (Makhoul et al 2019).…”

“…Additionally, many signaling molecules have been identified to be associated with the Golgi. Thus, it has been proposed that the Golgi could sense and transduce stress signals and therefore serves as a hub in the cellular signaling network (Farhan and Rabouille 2011;Mayinger 2011;Makhoul et al 2019).…”