Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles

Abstract

The structural integrity and functional stability of organelles are prerequisites for the viability and responsiveness of cells. Dysfunction of multiple organelles is critically involved in the pathogenesis and progression of various diseases, such as chronic obstructive pulmonary disease, cardiovascular diseases, infection, and neurodegenerative diseases. In fact, those organelles synchronously present with evident structural derangement and aberrant function under exposure to different stimuli, which might accelerate the corruption of cells. Therefore, the quality control of multiple organelles is of great importance in maintaining the survival and function of cells and could be a potential therapeutic target for human diseases. Organelle-specific autophagy is one of the major subtypes of autophagy, selectively targeting different organelles for quality control. This type of autophagy includes mitophagy, pexophagy, reticulophagy (endoplasmic reticulum), ribophagy, lysophagy, and nucleophagy. These kinds of organelle-specific autophagy are reported to be beneficial for inflammatory disorders by eliminating damaged organelles and maintaining homeostasis. In this review, we summarized the recent findings and mechanisms covering different kinds of organelle-specific autophagy, as well as their involvement in various diseases, aiming to arouse concern about the significance of the quality control of multiple organelles in the treatment of inflammatory diseases.Abbreviations: ABCD3: ATP binding cassette subfamily D member 3; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ARIH1: ariadne RBR E3 ubiquitin protein ligase 1; ATF: activating transcription factor; ATG: autophagy related; ATM: ATM serine/threonine kinase; BCL2: BCL2 apoptosis regulator; BCL2L11/BIM: BCL2 like 11; BCL2L13: BCL2 like 13; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CANX: calnexin; CAT: catalase; CCPG1: cell cycle progression 1; CHDH: choline dehydrogenase; COPD: chronic obstructive pulmonary disease; CSE: cigarette smoke exposure; CTSD: cathepsin D; DDIT3/CHOP: DNA-damage inducible transcript 3; DISC1: DISC1 scaffold protein; DNM1L/DRP1: dynamin 1 like; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 alpha kinase 3; EMD: emerin; EPAS1/HIF-2α: endothelial PAS domain protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FBXO27: F-box protein 27; FKBP8: FKBP prolyl isomerase 8; FTD: frontotemporal dementia; FUNDC1: FUN14 domain containing 1; G3BP1: G3BP stress granule assembly factor 1; GBA: glucocerebrosidase beta; HIF1A/HIF1: hypoxia inducible factor 1 subunit alpha; IMM: inner mitochondrial membrane; LCLAT1/ALCAT1: lysocardiolipin acyltransferase 1; LGALS3/Gal3: galectin 3; LIR: LC3-interacting region; LMNA: lamin A/C; LMNB1: lamin B1; LPS: lipopolysaccharide; MAPK8/JNK: mitogen-activated protein kinase 8; MAMs: mitochondria-associated membranes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MOD: multiple organelles dysfunction; MTPAP: mitochondrial poly(A) polymerase; MUL1: mitochondrial E3 ubiquitin protein ligase 1; NBR1: NBR1 autophagy cargo receptor; NLRP3: NLR family pyrin domain containing 3; NUFIP1: nuclear FMR1 interacting protein 1; OMM: outer mitochondrial membrane; OPTN: optineurin; PD: Parkinson disease; PARL: presenilin associated rhomboid like; PEX3: peroxisomal biogenesis factor 3; PGAM5: PGAM family member 5; PHB2: prohibitin 2; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RETREG1/FAM134B: reticulophagy regulator 1; RHOT1/MIRO1: ras homolog family member T1; RIPK3/RIP3: receptor interacting serine/threonine kinase 3; ROS: reactive oxygen species; RTN3: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SESN2: sestrin2; SIAH1: siah E3 ubiquitin protein ligase 1; SNCA: synuclein alpha; SNCAIP: synuclein alpha interacting protein; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TICAM1/TRIF: toll-like receptor adaptor molecule 1; TIMM23: translocase of inner mitochondrial membrane 23; TNKS: tankyrase; TOMM: translocase of the outer mitochondrial membrane; TRIM: tripartite motif containing; UCP2: uncoupling protein 2; ULK1: unc-51 like autophagy activating kinase; UPR: unfolded protein response; USP10: ubiquitin specific peptidase 10; VCP/p97: valosin containing protein; VDAC: voltage dependent anion channels; XIAP: X-linked inhibitor of apoptosis; ZNHIT3: zinc finger HIT-type containing 3.

Keywords: Lysophagy; mitophagy; nucleophagy; pexophagy; reticulophagy; ribophagy.

Figure 1.

Quality control of multiple organelles by organelle-specific autophagy. (A) Mitophagy is of great importance in maintaining functional homeostasis of mitochondria, which is initiated by PINK1-PRKN-dependent and independent pathways. It requires TOMM and TIMM23 for the import and subsequent cleavage of PINK1 in functional mitochondria, while its damage and dysfunction are followed with PINK1 accumulation on the OMM. VDAC, RHOT1, MFN1/2 proteins act as phosphoubiquitin substrates for PINK1- and PRKN-dependent mitophagy. Outer mitochondrial membrane (OMM) proteins, including BNIP3L, FUNDC1, BNIP3, AMBRA1, BCL2LI3, FKBP8, CHDH, and DISC1, can detect damaged mitochondria and mediate mitophagy by interacting with MAP1LC3B protein directly. In the pathogenesis of mitochondrial dysfunction, IMM proteins, such as PHB2 and cardiolipin, are responsible for the initiation of mitophagy after translocation from IMM to OMM. Additionally, several post-transcriptional modification mechanisms are involved in regulating mitophagy: SIAH1, MUL1 and ARIH1 function as E3 ubiquitin ligases that target OMM proteins, and TBK1 can enhance mitophagy by phosphorylating autophagic receptors. (B) Nucleophagy is programmed for selective removal of nuclear components through the process of autophagy. LMNB1 and chromatin can be degraded via autophagic machinery under senescence exposure. (C) Four receptors reportedly contribute to sequestration of isolated cargos of ER into autophagosomes, including RETREG1, SEC62, CCPG1, and RTN3, which are essential for initiation of reticulophagy after binding with MAP1LC3B. Both RETREG1 and SEC62 are primarily responsible for the turnover of ER sheets, while CCGP1 and RTN3 for the ER-tubules. (D) Pexophagy is deemed great potential in quality control of peroxisome and might be induced by following mechanisms: overexpression of PEX3, activation of ATG9A-TNKS/TNKS2-PEX14 complex, phosphorylation and mono-ubiquitination of PEX5 via ATM and the PEX2-PEX10-PEX12 complex, which recognized by SQSTM1, as well as ABCD3-dependent NBR1-MAP1LC3B pathway in overexpression of PEX2. (E) NUFIP1 serves as the major receptor for ribophagy machinery via specific binding to MAP1LC3B in the assist of ZNHIT3. USP10 and G3BP1 are found to be the mammalian homologs of ribophagy receptors in yeast, suggesting their potential roles in mammal ribophagy. (F) Lysophagy is indispensable for quality control of lysosomes. LGALS3 can sense damaged lysosomes and further recruit TRIM16 to initiate autophagic machinery by ubiquitinating autophagy associated molecules, including ULK1 and ATG16L1. In addition, FBXO27 can serve as a ubiquitinating glycoprotein, which regulate the recruitment of autophagic machinery in SQSTM1-MAP1LC3B pathway

Figure 2.

Quality control of multiple organelles through organelle-specific autophagy in infection and sepsis. (A) Nucleophagy is critically involved in preventing the invasion of pathogens by maintaining the integrity of epidermal barrier. (B) As initiated by LPS induced SESN2 upregulation, S. aureus-induced pneumonia as well as sepsis-related renal dysfunction, mitophagy is essential for the balance of inflammatory response and survival of cells in infection or septic challenge by limiting persistent NLRP3 inflammasome activation and eliminating damaged mitochondria respectively. (C) Induction of pexophagy attenuates LPS-mediated renal damage by restoring dysfunction of peroxisomes and redox imbalance. (D) Induction of lysophagy reportedly limits the invasion of intracellular M. tuberculosis in LGALS3- and TRIM16-dependent pathways, accompanied with recruitment of core autophagy proteins, including BECN1, ULK1 and ATG16L1. (E) Reticulophagy can promote the elimination of bacteria and virus via following mechanisms: resolving ER stress under exposure of Gram-positive bacteria and directly limiting replication of Zika, Dengue, and Ebola viruses. However, reticulophagy can be suppressed by NS2B3, a virus protease complex that may cleave RETREG1 within RHD domain