C. elegans RAB-35: Dual roles in apoptotic cell clearance

The phagocytic clearance of apoptotic cells is important for maintaining tissue homeostasis, and defects in phagocytic clearance can lead to inflammatory diseases and autoimmunity [1].While much is known about how apoptotic cells are cleared, there are many gaps in our knowledge.In this issue, Zheng Zhou and colleagues at Baylor College of Medicine report the identification of Rab35 as a new regulator of apoptotic cell clearance using the nematode Caenorhabditis elegans [2].C. elegans is an attractive model for the in vivo study of apoptotic cell clearance.During development, 131 somatic cells undergo apoptosis in an invariant manner and in the adult germline approximately 50% of germ cells die by apoptosis [3,4].In both cases, apoptotic cells are quickly engulfed by neighboring cells and degraded.Genetic screens for persistent apoptotic cells have identified genes and pathways that mediate apoptotic cell recognition, phagocytic engulfment, and phagosome maturation and degradation [3][4][5].Two parallel genetic pathways regulate apoptotic cell engulfment [3].Cell death abnormality (CED)-1, a scavenger receptor, functions with CED-6 engulfment adaptor PTB domain containing 1 (Gulp1) and the CED-7 adenosine triphosphate-binding cassette (ABC) transporter to recognize phosphatidylserine on dying cells.The other pathway, defined by the CED-2 adaptor protein, the CED-10 Rac1 guanosine triphosphate hydrolase (GTPase), and its bipartite guanine nucleotide exchange factor (GEF) CED-5 and CED-12, regulates actin polymerization.Loss of both pathways does not completely block apoptotic cell clearance [6], suggesting that there may be additional players.Once internalized, apoptotic cell-containing phagosomes undergo maturation.Phosphatidylinositol 4,5-phosphate (PI[4,5]P) is replaced with PI(3)P [7].This replacement is mediated in part by the loss of the myotubularin (MTM)-1 PI3-phosphatase, a PI(4,5)P effector, and the activity of the class II and class III PI3-kinases, phosphoinositide-3-kinase (PIKI)-1, and vacuolar protein sorting (VPS)-34, permitting the recruitment of PI(3)P binding proteins such as the sorting nexin (SNX)-1 [7][8][9].Several Rab GTPases control phagosome maturation and lysosomal degradation.During maturation, RAB-5 recruits the SAND-1/CCZ-1 GEF, which in turn recruits and activates 11], which along with RAB-2/uncoordinated (UNC)-108 and RAB-14 promote fusion with lysosomes [12].In an RNA-mediated interference (RNAi) screen for additional Rab GTPases that mediate apoptotic cell clearance, Haley and colleagues identify RAB-35 as a novel regulator of apoptotic cell clearance [2].C. elegans RAB-35 was previously found to regulate endosome recycling of the receptor-mediated endocytosis (RME)-2 yolk receptor in oocytes [13].In cells from other organisms, Rab35 has been implicated in regulation of the actin cytoskeleton and phagocytosis via regulation of the cell division cycle 42 (Cdc42), Rac1, and ADP-ribosylation factor 6 (Arf6) GTPases [14][15][16].

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.