The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. Over the past few years, there has been significant progress in elucidating the molecular organization and functions of the BBSome complex. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases. Here, we review the current literature on the structural assembly, transport regulation, and molecular functions of the BBSome, emphasizing its roles in cilium-related processes. We also provide perspectives on the pathological role of the BBSome in ciliopathies as well as how these can be exploited for therapeutic benefit.

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC′ cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8 ⁺ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells’ killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs’ functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC′ loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti–PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88 -knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88. Transforming growth factor-β (TGF-β), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-β-induced HSC activation and liver fibrosis. These findings reveal a previously unrecognized role for ciliary homeostasis in regulating HSC activation and identify the XIAP–IFT88 axis as a potential therapeutic target for liver fibrosis.

Cilia are highly specialized cellular projections emanating from the cell surface, whose defects contribute to a spectrum of diseases collectively known as ciliopathies. Intraflagellar transport protein 88 (IFT88) is a crucial component of the intraflagellar transport-B (IFT-B) subcomplex, a protein complex integral to ciliary transport. The absence of IFT88 disrupts the formation of ciliary structures; thus, animal models with IFT88 mutations, including the oak ridge polycystic kidney (ORPK) mouse model and IFT88 conditional allelic mouse model, are frequently employed in molecular and clinical studies of ciliary functions and ciliopathies. IFT88 plays a pivotal role in a variety of cilium-related processes, including organ fibrosis and cyst formation, metabolic regulation, chondrocyte development, and neurological functions. Moreover, IFT88 also exhibits cilium-independent functions, such as spindle orientation, planar cell polarity establishment, and actin organization. A deeper understanding of the biological events and molecular mechanisms mediated by IFT88 is anticipated to advance the development of diagnostic and therapeutic strategies for related diseases.

Production of melanin pigments is a protective mechanism of the skin against ultraviolet (UV)-induced damage and carcinogenesis. However, the molecular basis for melanogenesis is still poorly understood. Herein, we demonstrate a critical interplay between the primary cilium and the melanocortin 1 receptor (MC1R) signaling. Our data show that UV and α-melanocyte-stimulating hormone (α-MSH) trigger cilium formation in human melanocytes and melanoma cells. Deficiency of MC1R or the presence of its red hair color (RHC) variations significantly attenuates the UV/α-MSH-induced ciliogenesis. Further investigation reveals that MC1R enters the cilium upon UV/α-MSH stimulation, which is facilitated by the interaction of MC1R with the BBSome and the palmitoylation of MC1R. MC1R interacts with the BBSome through the second and third intercellular loops, which contain the common RHC variant alleles (R151C and R160W). These RHC variants of MC1R exhibit attenuated ciliary localization, and enforced ciliary localization of these variants elevates melanogenesis. Ciliary MC1R triggers a sustained cAMP signaling and selectively stimulates Sox9, which appears to up-regulate melanogenesis-related genes as the transcriptional cofactor for MITF. These findings reveal a previously unrecognized nexus between MC1R and cilia and suggest an important mechanism for RHC variant-related pigmentary defects.

Autophagy is a fundamental process for maintaining cell homeostasis, and STX17-mediated autophagosome–lysosome fusion is essential for cargo degradation and recycling. The translocation of STX17 to the autophagosome membrane is necessary for the fusion, yet the mechanism governing this process remains to be fully elucidated. Here, we show that following starvation, STX17 is acetylated at lysine 254 (K254), and this promotes the autophagosomal translocation of STX17 and subsequent autophagosome–lysosome fusion. Acetyltransferase GCN5 mediates STX17 K254 acetylation, which is counteracted by the deacetylase SIRT1. Moreover, autophagosomal translocation of K254-acetylated STX17 is mediated by myosin Ⅵ. Therefore, our research highlights the importance of acetylation and F-actin-based motor proteins in autophagosomal translocation of STX17 and autophagosome–lysosome fusion.