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. 2019 Dec 27;9(1):70. doi: 10.3390/cells9010070

Table 1.

The autophagy-related proteins involved in macrophage functions.

Category Functional Proteins in Macrophages Autophagy-Related Proteins Mechanism or Relationships Reference
Macrophage Receptors SR-A LC3 SR-A agonist inhibits autophagy by inhibiting LC3 [33]
MARCO LC3-ll/LC3-l MARCO is internalized as phagocytosis, accompanied by increased LC3-ll/LC3-l [34]
Dectin-1 Atg3, Atg7, DAP1, GABRAPL2, Optineurin, RGS9, P62 Autophagy process is activated and required in Dectin-1 induced unconventional protein secretion pathway. [38]
LC3, Atg5 Dectin-1 directs LC3 and ATG5 recruitment around phagosomes to facilitate MHC class ll into phagosome and help antigens presentation to T cells. [39]
TLRs LC3,
Beclin 1

  1. Interactions of Beclin 1 and Myd88 or Trif are increased after TLRs activation, so as to reduce the binding of Beclin 1 and Bcl-2, inducing autophagy.

  2. TRAF6 ubiquitinates Lysine (K)-linked ubiquitination of Beclin 1 and stimulates autophagy

 [41,42,43,44,45]
P62 LPS-induced TLR activation generates aggresome-like induced structures (ALIS), resulting in the recognition of p62 to induce autophagy [46]
NOD1, NOD2 Atg16L1 Interaction of NOD1 or NOD2 with Atg16L1 initiates autophagy [49]
NF-κB pathway NF-κB Beclin 1
Atg1

  1. NF-κB binding site is in the promoter of BECN1; p65/RelA upregulates BECN1 mRNA to activate autophagy.

  2. NF-κB factor Relish regulates autophagy by modulating Atg1

 [68,69]
IκB kinase (IKK) Atg5 Autophagy mediates IKK protein degradation after inhibiting Hsp90 by geldanamycin (GA).Inhibition of autophagy by knockout of Atg5 rescues IKK from GA-induced IKK degradation. [62]
NIK Atg5 Autophagy mediates NIK protein degradation after inhibiting Hsp90 by geldanamycin (GA). Blockage of autophagy by knockout of Atg5 inhibits GA-triggered NIK degradation. [63]
Inflammasome NLRP3 ULK1, P62

  1. Mitophagy is induced by knockout of Ripk2 by increasing the phosphorylating ULK1, which activates NLRP3 inflammasome.

  2. Palmitate induces the activation of NLRP3 inflammasome with increased ULK1 dependent mitophagy.

  3. NLRP3 inflammasome activation triggers autophagosome formation, and it assembles inflammasomes undergo ubiquitination and recruitment of p62 for delivery to autophagosomes.

  4. NLRP3 inflammasome is inhibited by clearance of stimuli via increased NF-κB-induced P62-dependent mitophagy.

 [71,89,90,93]
ASC P62 P62 is recruited to K63-linked ubiquitination of ASC for inducing ASC-targeted autophagosome formation and degradation. [91]
AIM2 P62 AIM2 interacts with E3 ubiquitin ligase to facilitate P62 recruitment of autophagic degradation. [92]
IL-1β LC3

  1. Pro-IL-1β is sequestered into autophagosome for autophagical degradation, so that to inhibit mature IL-1β generation and secretion.

  2. IL-1β works with TRIM16 and R-SNARE SEC22B and is delivered into LC3-positive autophagic membranes for secretion.

  3. IL-1β secretion is increased after autophagy activation with the augmented colocalization of IL-1β and LC3, but it will be decreased when autophagy is inhibited.

 [111,112,113]
Polarization iNOS LC3, Atg5

  1. MiR-326 upregulation promotes autophagy and downregulates iNOS expressioin in mice brain.

  2. Glucocorticoids inhibit iNOS expression and induces autophagy.

  3. Activation of autophagy suppresses iNOS expression in microglia; Depletion of Atg5 increases iNOS expression.

 [104,105,106]
Arginase LC3, P62

  1. Hepatoma tumor cell condition medium induces macrophage M2-like phenotype (increased Arginase 1 expression), accompanied by increased selective autophagy.

  2. Recombinant human arginase (rhArg) induces autophagy in lymphoma cells.

 [97,107]
CD206 LC3 CCL2 or IL-6 induces autophagy, companying with the macrophage polarization toward CD206+ M2-type activation. [102]
TLR 9 pathway IFN-α LC3, Atg7 IFN-α secretion is required for LC3-associated phagocytosis (LAP). [53]
IKKα, IRF7 and TRAF3 LC3, Atg5 LC3 interacts with IKKα after TLR9 activation, and it is further associated with IRF7 and TRAF3 to facilitate type 1 IFN production. [98]
LC3-associated phagocytosis (LAP) PI(3)P Beclin1, UVRAG, Vps34, Atg5, Atg3, Atg12, and Atg16L1 Autophagical genes, such as Beclin1, UVRAG, Vps34, Atg5, Atg3, Atg12 and Atg16L1 are required for LAP to generate PI (3) P and facilitate maturation. [32]
Xenophagy cGAS, Nod1 and Nod2, Atg16L1, LC3, NDP52, p62, optineurin, NBR1, V-ATPase

  1. Escaped bacterial DNA was recognized by cytosolic sensor cGAS, subsequently, inducing xenophagy via recruiting p62 and NDP52.

  2. NOD1 and NOD2 sense invasive bacterial and induced xenophagy by recruiting Atg16L1 at the site of bacterial entry.

  3. Neighbor of BRCA1 gene 1 (NBR1) and optineurin also serve the xenophagy process.

  4. V-ATPase senses the membrane damage and recruit ATG16L1 to trigger xenophagy.

 [49,120,123,124,125,130]
RIG-1 pathway RIG-1 like receptors (RIRs), MAVS Atg5-Atg12, Atg7, Beclin-1

  1. Atg5, Atg12, and Atg7 negatively regulate RLR-dependent signaling.

  2. Atg5-Atg12 conjugates interact with RIG1 and MAVS and inhibit RLR-dependent antiviral signaling.

  3. RIG-1 RNA sensing pathway induces autophagy via a MAVS-TRAF6-Beclin-1 axis.
CGAS-STING pathway cGAS, cGAMP, STING, TRIM14 ULK1, Beclin-1, p62, LC3

  1. cGAMP in STING pathway induces autophagy kinase ULK1, resulting in the inhibition of downstream signaling.

  2. cGAS interacts with Beclin-1 to enhance cytosolic microbial DNAs degradation via autophagy.

  3. TRIM14 stabilizes cGAS by recruiting USP14 and cleaving the lysine 48-linked ubiquitin, resulting in inhibition of p62-mediated autophagic degradation of cGAS.

  4. STING localized on the ER-Golgi body intermediate compartment (ERGIC) activates autophagy to eliminate DNA and viruses by inducing LC3 lipidation, which is dependent on ATG5 and WIPI2, not the ULK and VPS34 complex.