The Bardet–Biedl syndrome complex component BBS1 controls T cell polarity during immune synapse assembly

Abstract

Components of the intraflagellar transport (IFT) system that regulates the assembly of the primary cilium are co-opted by the non-ciliated T cell to orchestrate polarized endosome recycling and to sustain signaling during immune synapse formation. Here we have investigated the potential role of BBS1, an essential core component of the Bardet-Biedl syndrome complex that cooperates with the IFT system in ciliary protein trafficking, in the assembly of the T cell synapse. We demonstrate that BBS1 allows for centrosome polarization towards the immune synapse. This function is achieved through the clearance of centrosomal F-actin and its positive regulator WASH, a process that we demonstrate to be dependent on the proteasome. We show that BBS1 regulates this process by coupling the 19S proteasome regulatory subunit to the microtubule motor dynein for its transport to the centrosome. Our data identify the ciliopathy-related protein BBS1 as a new player in T cell synapse assembly that acts upstream of the IFT system to set the stage for polarized vesicular trafficking and sustained signaling.

Lymphocyte Polarization During Immune Synapse Assembly: Centrosomal Actin Joins the Game

“…Consistent with this evidence, we observed that the centrosomal 19S RP pool increases early during IS formation, to progressively return to baseline with IS maturation (23). Additionally, we found that the centrosome failed to polarize to the IS in T cells pretreated with proteasome inhibitors and that the mislocation of the centrosome in these cells is paralleled by F-actin accumulation at the centrosome, supporting a role for the centrosomal proteasome in IS formation.…”

“…In recent years new, unexpected players have been identified in the mechanisms that regulate centrosomal F-actin clearance and centrosome polarization during IS assembly. We and Ibañez-Vega et al have implicated the ubiquitin-proteasome system (UPS) in this process (23,58,59) (Figure 1). The UPS is a major degradation pathway in eukaryotic cells and is responsible for proteolysis of cytosolic proteins regulating a variety of cellular processes.…”

“…In B lymphocytes the intracellular distribution of the proteasome is regulated by the proteasome adapter and scaffold protein Ecm29 during B cell IS formation, allowing a sequential recruitment of the proteasome to the centrosome and then to the IS, which is crucial for F-actin reorganization at both locations (58,59). In T lymphocytes proteasome-mediated degradation of unknown targets at early stages of IS assembly is dependent on the transport of the 19S regulatory particle (RP) to the centrosome, which is paralleled by an active degradation of K48-linked polyubiquitylated proteins (K48 Ub) (23). The contribution extent as well as the sequential implication of these pathways to the process remain to be elucidated.…”

“…The mechanisms linking the centrosomal proteasome to the local F-actin pool remain unknown. While actin depletion is regulated by the balance in the depolymerization and de novo synthesis of actin filaments, proteasome-regulated and centrosome-associated actin nucleators, such as Arp2/3 and its activator WASH [assembly and activity of the WASH complex are extensively reviewed in (78)], which become depleted during IS assembly (23), may represent potential targets of the centrosomal proteasome. Particularly interesting candidates are the proteasome-regulated E3 ligase TRIM27, which activates WASH through K63 monoubiquitination (79), and the centriolar satellite protein PCM1 (80), which recruits Arp2/3 and WASH to the T cell centrosome (50).…”

“…Here, we will summarize how actin dynamics at the synaptic and centrosomal areas regulate IS assembly. We will then describe the emerging role of the ubiquitin-proteasome system (UPS) in centrosomal Factin remodeling, focusing on our recent findings that identify the ciliary protein Bardet-Biedl Syndrome 1 (BBS1) as a new regulator of T cell polarity during IS formation (23).…”