bims-nocaut 2022-08-28 papers

Issue of 2022‒08‒28
four papers selected by
Quentin Frenger
University of Strasbourg

Cells. 2022 Aug 12. pii: 2514. [Epub ahead of print]11(16):

Autophagy, Acute Pancreatitis and the Metamorphoses of a Trypsinogen-Activating Organelle.

Svetlana Voronina, Michael Chvanov, Francesca De Faveri, Ulrike Mayer, Tom Wileman, David Criddle, Alexei Tepikin.

Recent studies have highlighted the importance of autophagy and particularly non-canonical autophagy in the development and progression of acute pancreatitis (a frequent disease with considerable morbidity and significant mortality). An important early event in the development of acute pancreatitis is the intrapancreatic activation of trypsinogen, (i.e., formation of trypsin) leading to the autodigestion of the organ. Another prominent phenomenon associated with the initiation of this disease is vacuolisation and specifically the formation of giant endocytic vacuoles in pancreatic acinar cells. These organelles develop in acinar cells exposed to several inducers of acute pancreatitis (including taurolithocholic acid and high concentrations of secretagogues cholecystokinin and acetylcholine). Notably, early trypsinogen activation occurs in the endocytic vacuoles. These trypsinogen-activating organelles undergo activation, long-distance trafficking, and non-canonical autophagy. In this review, we will discuss the role of autophagy in acute pancreatitis and particularly focus on the recently discovered LAP-like non-canonical autophagy (LNCA) of endocytic vacuoles.

Keywords: ATG8; CASM; LAP; LAP-like non-canonical autophagy; LC3; LC3-associated phagocytosis; LNCA; acute pancreatitis; autophagy; cholecystokinin; endocytic vacuole; non-canonical autophagy; pancreatic acinar cell; trypsin; trypsinogen; zymogen granule

DOI: https://doi.org/10.3390/cells11162514

Pathogens. 2022 Jul 30. pii: 863. [Epub ahead of print]11(8):

LC3-Associated Phagocytosis in Bacterial Infection.

Jin Yuan, Qiuyu Zhang, Shihua Chen, Min Yan, Lei Yue.

LC3-associated phagocytosis (LAP) is a noncanonical autophagy process reported in recent years and is one of the effective mechanisms of host defense against bacterial infection. During LAP, bacteria are recognized by pattern recognition receptors (PRRs), enter the body, and then recruit LC3 onto a single-membrane phagosome to form a LAPosome. LC3 conjugation can promote the fusion of the LAPosomes with lysosomes, resulting in their maturation into phagolysosomes, which can effectively kill the identified pathogens. However, to survive in host cells, bacteria have also evolved strategies to evade killing by LAP. In this review, we summarized the mechanism of LAP in resistance to bacterial infection and the ways in which bacteria escape LAP. We aim to provide new clues for developing novel therapeutic strategies for bacterial infectious diseases.

Keywords: LC3-associated phagocytosis; bacterial infection; immune evasion; phagocyte

DOI: https://doi.org/10.3390/pathogens11080863

Autophagy. 2022 Aug 26.

LEAP: a novel LC3C-dependent pathway connects autophagy, endocytic trafficking and signaling.

Paula P Coelho, Morag Park.

Macroautophagy/autophagy acts to promote homeostasis and is increasingly understood to selectively target cargo for degradation. The LC3-family of proteins mediate diverse yet distinct cargo recruitment to phagophores. However, what underlies specificity for cargo engagement among LC3 proteins is poorly understood. Using an unbiased protein interaction screen of LC3B and LC3C we uncover a novel LC3C-endocytic-associated-pathway (LEAP) that recruits selective plasma membrane (PM) cargo to phagophores. We show LC3C but not LC3B localizes to peripheral endosomes and engages proteins that traffic between the PM, endosomes and autophagosomes. We establish that endocytic LC3C binds cargo internalized from the PM, including MET receptor tyrosine kinase and TFRC (transferrin receptor), and targets them towards autophagic degradation. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signaling and autophagic degradation with important implications in cancer and other disease states.

Keywords: Atg8-orthologs; LC3C; MET-RTK; autophagy; endocytic trafficking; selective cargo recruitment; signalophagy

DOI: https://doi.org/10.1080/15548627.2022.2117973

Autophagy. 2022 Aug 25. 1-17

Transcriptomic analysis of pathways associated with ITGAV/alpha(v) integrin-dependent autophagy in human B cells.

Virginia Muir, Sara Sagadiev, Shuozhi Liu, Ursula Holder, Andrea M Armendariz, Emmaline Suchland, Iana Meitlis, Nathan Camp, Natalia Giltiay, Jenny M Tam, Ethan C Garner, Carl N Wivagg, Donna Shows, Richard G James, Adam Lacy-Hulbert, Mridu Acharya.

Macroautophagy/autophagy proteins have been linked with the development of immune-mediated diseases including lupus, but the mechanisms for this are unclear due to the complex roles of these proteins in multiple immune cell types. We have previously shown that a form of noncanonical autophagy induced by ITGAV/alpha(v) integrins regulates B cell activation by viral and self-antigens, in mice. Here, we investigate the involvement of this pathway in B cells from human tissues. Our data reveal that autophagy is specifically induced in the germinal center and memory B cell subpopulations of human tonsils and spleens. Transcriptomic analysis show that the induction of autophagy is related to unique aspects of activated B cells such as mitochondrial metabolism. To understand the function of ITGAV/alpha(v) integrin-dependent autophagy in human B cells, we used CRISPR-mediated knockdown of autophagy genes. Integrating data from primary B cells and knockout cells, we found that ITGAV/alpha(v)-dependent autophagy limits activation of specific pathways related to B cell responses, while promoting others. These data provide new mechanistic links for autophagy and B-cell-mediated immune dysregulation in diseases such as lupus.

Keywords: Autophagy; B cells; TLR signaling; cell-cycle; mitophagy; non-canonical autophagy

DOI: https://doi.org/10.1080/15548627.2022.2113296