A P O L 3 promotes P I 4 P synthesis by P I 4 K B at the Golgi, a process supported by calcium and N C S 1, leading to membrane fission and secretion. Pathogen D N A–triggered STING activation induces type I interferon signaling, which together with A P O L 1-dependent Golgi vesicle trafficking promotes the movement of A T G 9 A vesicles carrying P I 4 K B and A R F 1. A R F 1 activation, induced by type I interferon signaling, A P O L 3 loss, lysosomal damage, or possibly phagosomal cardiolipin, releases A P O L 3 from P I 4 K B and stimulates P I 4 P production on A T G 9 A vesicles. These vesicles localize to mitochondria–E R contact sites (M E R C S), where P I 4 P promotes mitochondrial membrane fission to initiate mitophagy. A P O L 3 interaction with V A M P 8 supports cardiolipin-dependent membrane fusion for mitophagy completion, while A P O L 3 or m A P O L 7 C can form megapores in mitochondrial membranes to promote apoptosis. In phagosomal membranes, cardiolipin insertion may trigger A P O L 3 or m A P O L 7 C-mediated megapore formation, facilitating antigen cross-presentation and coupling to apoptosis.
APOL1 and APOL3 involvement in inflammation and antigen cross-presentation. The cellular detection of pathogen DNA triggers activation, then degradation, of the inflammation stimulator STING. This occurs through PI4P-mediated translocation of STING from the ER to the Golgi, followed by STING oligomerization at the Golgi, then STING translocation from the Golgi to MERCS (13). APOL3 could be involved in this process through its key role in promotion of PI4P synthesis by the PI4KB kinase at the Golgi. Either IFN-I signalling or APOL3 downregulation (loss or inactivation) triggers the traffic of Golgi-derived ATG9A vesicles carrying PI4KB and ARF1 to MERCS. STING also traffics in such vesicles for its degradation, but whether this involves APOL1 and/or APOL3 is not known. If activated by IFN-I, ARF1 is expected to dissociate APOL3 from PI4KB (24), allowing PI4KB release from the Golgi. ARF1-induced PI4KB activity at MERCS initiates mitophagy through mitochondrion fission. If trafficked to MERCS following APOL3 downregulation, thus, in the absence of IFN-I signalling, inactivated ARF1 may not allow efficient induction of mitophagy, causing podocyte dysfunctions such as occurs in APOL1-mediated nephropathy (24). Mitophagy completion results from mitophagosome fusion with endolysosomes, which involves APOL3 interaction with the endosomal fusion protein VAMP8 (24). Thus, APOL3 and STING are markers of both initiation and termination of inflammation. Cardiolipin insertion in the DC phagosomal membrane, occurring during phagocytosis of pathogens, could hypothetically trigger APOL3- or mAPOL7C-driven megapore formation, allowing antigen cross-presentation. Accordingly, APOL3 and mAPOL7C are also involved in apoptotic megapore formation in cardiolipin-containing mitochondrial outer membrane, either following IFN-I signalling or lysosomal damage. In both cases, APOL3 may interact with VAMP8, known as APOL3 to be involved in both mitophagy and antigen cross-presentation.