TANGO2-related rhabdomyolysis symptoms are associated with abnormal autophagy functioning.

Patients with pathogenic variants in the gene suffer from severe and recurrent rhabdomyolysis episodes precipitated by fasting. Autophagy functioning was analyzed , in primary skeletal myoblasts from TANGO2 patients, in basal and fasting conditions, and mutations were associated with reduced LC3-II levels upon starvation. In zebrafish larvae, inhibition induced locomotor defects which were exacerbated by exposure to atorvastatin, a compound known to cause rhabdomyolysis.

FDX2 and ISCU Gene Variations Lead to Rhabdomyolysis With Distinct Severity and Iron Regulation.

Background And Objectives: To determine common clinical and biological traits in 2 individuals with variants in and , displaying severe and recurrent rhabdomyolyses and lactic acidosis.

Methods: We performed a clinical characterization of 2 distinct individuals with biallelic or variants from 2 separate families and a biological characterization with muscle and cells from those patients.

Results: The individual with variants was clinically more affected than the individual with variants.

The role of MHC class I recycling and Arf6 in cross-presentation by murine dendritic cells.

Cross-presentation by MHC class I molecules (MHC-I) is critical for priming of cytotoxic T cells. Peptides derived from cross-presented antigens can be loaded on MHC-I in the endoplasmic reticulum and in endocytic or phagocytic compartments of murine DCs. However, the origin of MHC-I in the latter compartments is poorly understood.

Endocytic Recycling of MHC Class I Molecules in Non-professional Antigen Presenting and Dendritic Cells.

Major histocompatibility complex class I (MHC I) molecules are glycoproteins that display peptide epitopes at the cell surface of nucleated cells for recognition by CD8 T cells. Like other cell surface receptors, MHC class I molecules are continuously removed from the surface followed by intracellular degradation or recycling to the cell surface, in a process likely involving active quality control the mechanism of which remains unknown. The molecular players and pathways involved in internalization and recycling have previously been studied in model cell lines such as HeLa.

Innate Immune Signals Induce Anterograde Endosome Transport Promoting MHC Class I Cross-Presentation.

Both cross-presentation of antigens by dendritic cells, a key pathway triggering T cell immunity and immune tolerance, and survival of several pathogens residing in intracellular vacuoles are intimately linked to delayed maturation of vesicles containing internalized antigens and microbes. However, how early endosome or phagosome identity is maintained is incompletely understood. We show that Toll-like receptor 4 (TLR4) and Fc receptor ligation induces interaction of the GTPase Rab14 with the kinesin KIF16b mediating plus-end-directed microtubule transport of endosomes.

Impact of the TAP-like transporter in antigen presentation and phagosome maturation.

Cross-presentation is thought to require transport of proteasome-generated peptides by the TAP transporters into MHC class I loading compartments for most antigens. However, a proteasome-dependent but TAP-independent pathway has also been described. Depletion of the pool of recycling cell surface MHC class I molecules available for loading with cross-presented peptides might partly or largely account for the critical role of TAP in cross-presentation of phagocytosed antigens.

MHC Class I Cross-Presentation: Stage Lights on Sec22b.

Efficient (cross-)presentation of antigens internalized by dendritic cells (DCs) requires vesicular communication between the early secretory and the endocytic/phagocytic pathways, in which the Sec22b protein has been suggested to have a key role. Here, we undertake a critical assessment of two new studies that evaluate the role of Sec22b using gene-targeted mice and come to contradictory conclusions.

Dissociation of β2-microglobulin determines the surface quality control of major histocompatibility complex class I molecules.

Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2K(b) class I proteins from the cell surface.