bims-nocaut 2023-11-12 papers

Issue of 2023‒11‒12
two papers selected by
Quentin Frenger, University of Strasbourg

Cells. 2023 Nov 02. pii: 2566. [Epub ahead of print]12(21):

The Small GTPase Rab7 Regulates Antigen Processing in B Cells in a Possible Interplay with Autophagy Machinery.

Marika Runsala, Elina Kuokkanen, Eveliina Uski, Vid Šuštar, Meryem Özge Balci, Johanna Rajala, Vilma Paavola, Pieta K Mattila.

In B cells, antigen processing and peptide-antigen (pAg) presentation is essential to ignite high-affinity antibody responses with the help of cognate T cells. B cells efficiently internalize and direct specific antigens for processing and loading onto MHCII. This critical step, which enables pAg presentation, occurs in MHCII compartments (MIICs) which possess the enzymatic machinery for pAg loading on MHCII. The intracellular transport systems that guide antigen and maintain this unique compartment remain enigmatic. Here, we probed the possible functional role of two known endosomal proteins, the Rab family small GTPases Rab7 and Rab9, that are both reported to colocalize with internalized antigen. As compared to Rab9, we found Rab7 to exhibit a higher overlap with antigen and MIIC components. Rab7 also showed a higher association with antigen degradation. The inhibition of Rab7 drastically decreased pAg presentation. Additionally, we detected the strong colocalization of perinuclearly clustered and presumably MIIC-associated antigen with autophagy protein LC3. When we pharmacologically inhibited autophagy, pAg presentation was inhibited. Together, our data promote Rab7 as an important regulator of antigen processing and, considering the previously reported functions of Rab7 in autophagy, this also raises the possibility of the involvement of autophagy-related machinery in this process.

Keywords: B cell activation; B cell receptor; BCR; MHCII; Rab7; adaptive immune system; antigen processing; autophagy; endosomes; lysosomes; vesicle traffic

DOI: https://doi.org/10.3390/cells12212566

Dev Cell. 2023 Oct 29. pii: S1534-5807(23)00526-9. [Epub ahead of print]

V-ATPase recruitment to ER exit sites switches COPII-mediated transport to lysosomal degradation.

Yiwei Sun, Xi'e Wang, Xiaotong Yang, Lei Wang, Jingjin Ding, Chih-Chen Wang, Hong Zhang, Xi Wang.

Endoplasmic reticulum (ER)-phagy is crucial to regulate the function and homeostasis of the ER via lysosomal degradation, but how it is initiated is unclear. Here we discover that Z-AAT, a disease-causing mutant of α1-antitrypsin, induces noncanonical ER-phagy at ER exit sites (ERESs). Accumulation of misfolded Z-AAT at the ERESs impairs coat protein complex II (COPII)-mediated ER-to-Golgi transport and retains V0 subunits that further assemble V-ATPase at the arrested ERESs. V-ATPase subsequently recruits ATG16L1 onto ERESs to mediate in situ lipidation of LC3C. FAM134B-II is then recruited by LC3C via its LIR motif and elicits ER-phagy leading to efficient lysosomal degradation of Z-AAT. Activation of this ER-phagy mediated by the V-ATPase-ATG16L1-LC3C axis (EVAC) is also triggered by blocking ER export. Our findings identify a pathway which switches COPII-mediated transport to lysosomal degradation for ER quality control.

Keywords: ATG16L1; COPII; ER exit sites; ER-phagy; LC3C; Sec24C; V-ATPase; autophagy; protein quality control; α1 antitrypsin

DOI: https://doi.org/10.1016/j.devcel.2023.10.007