Multipronged regulation of autophagy and apoptosis: emerging role of TRIM proteins

Abstract

TRIM proteins are characterized by their conserved N-terminal RING, B-box, and coiled-coil domains. These proteins are efficient regulators of autophagy, apoptosis, and innate immune responses and confer immunity against viruses and bacteria. TRIMs function as receptors or scaffold proteins that target substrates for autophagy-mediated degradation. Most TRIMs interact with the BECN1-ULK1 complex to form TRIMosomes, thereby efficiently targeting substrates to autophagosomes. They regulate the functions of ATG proteins through physical interactions or ubiquitination. TRIMs affect the lipidation of MAP1LC3B1 to form MAP1LC3B2, which is a prerequisite for phagophore and autophagosome formation. In addition, they regulate MTOR kinase and TFEB, thereby regulating the expression of ATG genes. TRIM proteins are efficient regulators of apoptosis and are crucial for regulating cell proliferation and tumor formation. Many TRIM proteins regulate intrinsic and extrinsic apoptosis via the cell surface receptors TGFBR2, TNFRSF1A, and FAS. Mitochondria modulate the anti- and proapoptotic functions of BCL2, BAX, BAK1, and CYCS. These proteins use a multipronged approach to regulate the intrinsic and extrinsic apoptotic pathways, culminating in coordinated activation or inhibition of the initiator and executor CASPs. Furthermore, TRIMs can have a dual effect in determining cell fate and are therefore crucial for cellular homeostasis. In this review, we discuss mechanistic insights into the role of TRIM proteins in regulating autophagy and apoptosis, which can be used to better understand cellular physiology. These findings can be used to develop therapeutic interventions to prevent or treat multiple genetic and infectious diseases.

Keywords: Apoptosis; Autophagosome; Autophagy; Autophagy receptor; BECN1; E3-Ub ligase; TP53; TRIM proteins; ULK1; Ubiquitination.

Fig. 1

TRIM proteins possess a unique RBCC domain at their N-terminus and regulate various biological processes. a Domain organization of TRIM proteins at the N- and C-termini. The N-terminus contains a conserved RBCC domain, whereas the C-terminus contains variable domains required for protein‒protein interactions and substrate selection. b TRIM5α provides immunity against retroviruses, including HIV-1. It forms a hexagonal ring around the capsid, preventing the release of the genome and targeting the autophagosome-mediated degradation of HIV-1. c TRIM proteins regulate signaling events emanating from IFN receptors, TLRs, and RIGI receptors and activate IFN and NFKB signaling to produce proinflammatory cytokines. d TRIMs interact with the core components of autophagy, such as the BECN1-ULK1 autophagy-initiating complex and Ub-interacting autophagy receptors, to efficiently target substrates to autophagosomes for lysosome-mediated degradation. e TRIM proteins are essential regulators of cell proliferation, differentiation, and apoptosis. TRIM; Tripartite motif containing, RBCC; RING, B-box, Coiled-coil, TRIM5α; Tripartite motif containing 5α, HIV-1, Human immune deficiency virus-1, IFN; Interferon, TLR; Toll-like receptor, TLR3; Toll-like receptor 3, RIGI; RNA sensor RIG-I, NFKB; Nuclear factor kappa B, BECN1; Beclin 1, ULK1; Unc-51 like autophagy activating kinase 1, TLR3; Toll-like receptor 3, RING; Really interesting new gene, IFNR; Interferon production regulator, IRF3; Interferon regulatory factor 3, IRF5; Interferon regulatory factor 5, IRF7; Interferon regulatory factor 7, AR; Autophagy receptor, CALCOCO2; Calcium binding and coiled-coil domain 2, NBR1; NBR1 autophagy cargo receptor, SQSTM1; Sequestome 1, TAX1BP1; Tax1 binding protein 1, OPTN; Optineurin, TRIM16; Tripartite motif containing 16, MAP1LC3; Microtubule associated protein 1 light chain 3, GABARAP; GABA type A receptor-associated protein, STAT; Signal transducer and activator of transcription

Fig. 2

RING domain-containing TRIMs act as E3-Ub ligase and conjugate Ub to the target substrate, regulating autophagy. a Three enzymes catalyze the transfer of Ub to the target substrate. E1 catalyzes the conversion of Ub to E2 via ATP hydrolysis. E3-Ub ligases containing RING domains directly transfer Ub to the target substrate, whereas HECT and RBR E3-Ub ligases form E3-Ub intermediates before transferring Ub to the target substrates. b Various signal inputs converge on the main autophagy regulator MTOR, such as PIK3CA, TP53, MAPK3/MAPK1, hunger, and PRKAA2/AMPK. Activation of the MTOR kinase complex inhibits autophagy by inducing inhibitory phosphorylation of the autophagy-initiating kinase ULK1. PRKAA2 activated autophagy by phosphorylating ULK1. TRIM proteins regulate various steps of canonical autophagy, including autophagy initiation, phagophore formation, MAP1LC3 conjugation, and efficient targeting of substrates to autophagosomes via autophagy receptors and Ub. Autophagosomes fuse with lysosomes to form autolysosomes, which degrade the entrapped cargo materials. TRIM; Tripartite motif containing, Ub; Ubiquitin, ATP; Adenosine triphosphate, RING; Really interesting new gene, HECT; Homologous to the E6-AP carboxyl terminus, RBR; RING-in-between-RING, MTOR; Mechanistic target of rapamycin kinase, PIK3CA; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, TP53; Tumor protein 53, MAPK3/MAPK1; mitogen-activated protein kinase 3/1, PRKAA2/AMPK; Protein kinase AMP-activated catalytic subunit alpha 2, ULK1; Unc-51 like autophagy activating kinase 1, MAP1LC3B2; Microtubule associated protein 1 light chain 3 beta 2, AKT1; AKT serine/threonine kinase 1, PPi; Inorganic pyrophosphate, AMP; Adenosine monophosphate, RUBCN; rubicon autophagy regulator, BCL2; BCL2 apoptosis regulator, ATG13; Autophagy related 13, RB1CC1; RB1 inducible coiled-coil 1, ATG10; Autophagy related 10, ATG7; Autophagy related 7, ATG12; Autophagy related 12, ATG14; Autophagy related 14, PIK3C3; Phosphatidylinositol 3-kinase catalytic subunit type 3, PIK3R4; phosphoinositide-3-kinase regulatory subunit 4, BECN1; Beclin 1, ATG16L1; Autophagy related 16 like 1, ATG5; Autophagy related 5, AR; Autophagy receptor, CALCOCO2; Calcium binding and coiled-coil domain 2, NBR1; NBR1 autophagy cargo receptor, SQSTM1; Sequestome 1, TAX1BP1; Tax1 binding protein 1, OPTN; Optineurin, TRIM16; Tripartite motif containing 16, ATG10; Autophagy related 10, ATG7; Autophagy related 7, ATG12; Autophagy related 12, ATG13; Autophagy related 13, DUB; Deubiquitinase

Fig. 3

TRIM proteins regulate autophagy by modulating the MTOR complex, TFEB, ULK1-BECN1 complex, and MAP1LC3 conjugation. TRIM proteins regulate autophagy at various steps, including the activity of MTOR, TFEB, the BECN1-ULK1 complex, and the conjugation of MAP1LC3 to form MAP1LC3I and MAP1LC3II to form phagophores and autophagosomes. Autophagosomes fuse with lysosomes to form autolysosomes, which breakdown and recycle cargo materials and autophagosomes. Autophagosomes fuse with lysosomes to form autolysosomes, degrade cargo materials, and recycle. MTOR; Mechanistic target of rapamycin kinase, TFEB; Transcription factor EB, ULK1; Unc-51 like autophagy activating kinase 1, BECN1; Beclin 1, MAP1LC3B2; Microtubule associated protein 1 light chain beta 2, TRIM; Tripartite motif containing, Ub; Ubiquitin, AR; Autophagy receptor, CALCOCO2; Calcium binding and coiled-coil domain 2, NBR1; NBR1 autophagy cargo receptor, SQSTM1; Sequestome 1, TAX1BP1; Tax1 binding protein 1, OPTN; Optineurin, TRIM16; Tripartite motif containing 16, Autophagy related 14, PIK3C3; Phosphatidylinositol 3-kinase catalytic subunit type 3, PIK3R4; phosphoinositide-3-kinase regulatory subunit 4, ATG5; Autophagy related 5, ATG10; Autophagy related 10, ATG7; Autophagy related 7, ATG12; Autophagy related 12, ATG13; Autophagy related 13, ATG4; Autophagy related 4, ATG3; Autophagy related 3, RB1CC1; RB1 inducible coiled-coil 1, RAB7A; RAB7A, member RAS oncogene family

Fig. 4

TRIM protein-mediated autophagy is involved in regulating immunity against various bacteria and viruses. a Autophagy involves the initiation of phagophores regulated by ULK1. Class III phosphatidylinositol kinases, the ULK1-BECN1 complex, and MTOR kinase regulate the initiation of autophagy and the formation of phagophores. MTOR activity is regulated by PRKAA2, PIK3CA-AKT1 signaling, and MAPK3/MAPK1 signaling. The phagophores mature into autophagosomes and fuse with lysosomes to form autolysosomes. TRIM proteins target bacteria and viruses to autophagosomes to degrade and activate innate immune signaling. b TRIM proteins activate inflammasome complexes and convert pro-CASP1 to active CASP1, producing the proinflammatory cytokines IL1B and IL18. c TRIMs regulate the KEAP1-SQSTM1-ZNRF2 signaling axis and ZNFR2-mediated transcription. TRIM proteins also regulate IFN and NFKB signaling cascades to induce the production of proinflammatory cytokines. TRIM; Tripartite motif containing, ULK1; Unc-51 like autophagy activating kinase 1, BECN1; Beclin 1, MTOR; Mechanistic target of rapamycin kinase, PRKAA2; Protein kinase AMP-activated catalytic subunit alpha 2, PIK3CA; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, MAPK3/1; Mitogen-activated protein kinase 3/1, CASP; Caspase, IL1B; Interleukin 1 beta, IL18; Interleukin 18, KEAP1; Kelch like ECH associated protein 1, SQSTM1; Sequestome 1, ZNRF2; Zinc and ring finger 2, IFN; Interferon, NFKB; Nuclear factor kappa B, AKT1; AKT serine/threonine kinase 1, S. typhi; Salmonella typhi, M. tb; Mycobacterium tuberculosis, IAV; Influenza A virus, HSV1; Herpes simplex virus 1, EMCV; Encephalomyocarditis virus, HIV-1; Human immune deficiency virus, E71, Enterovirus 71, NLRP1; NLR family pyrin domain containing 1, NLRP3; NLR family pyrin domain containing 3, AIM2; Absent in melanoma 2, CASP1; Caspase 1, TLR; Toll-like receptor, RIGI; RNA sensor RIG-I, IFIH1; Interferon induced with helicase C domain 1, IKBKB; Inhibitor of nuclear factor kappa B kinase subunit beta, IRF3; Interferon regulatory factor 3, IRF8; Interferon regulatory factor 8

Fig. 5

TRIM proteins regulate extrinsic and intrinsic apoptosis via diverse mechanisms. TRIMs regulate death receptor-mediated apoptosis by regulating the activation of initiator and executor CASPs and MAPK signaling cascades. TRIMs also regulate intrinsic apoptosis mediated by the mitochondria and the pro- and anti-apoptotic proteins BAX, BAK1, and BCL2. They induce the formation of mitochondrial pores to release CYCS, thereby inducing the formation of apoptosomes and the activation of CASP9 and CASP3. Some TRIMs activate anti-apoptotic BCL2 to inhibit mitochondrial pore formation and CYCS release, thereby preventing apoptosome formation and CASP9 activation. Several TRIM proteins are localized in the nucleus to regulate gene expression mediated by TP53, NFATs, and NFKB. NFKB; Nuclear factor kappa B, TGFB2; Transforming growth factor beta 2, FASLG; Fas ligand, TNF; Tumor necrosis factor, TGFBR2; Transforming growth factor beta receptor 2, FAS; Fas cell surface death receptor, TNFRSF1A; TNF receptor superfamily member 1A, PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, DIAPH1; DIAPH1, APAF1; Apoptotic peptidase activating factor 1, DAXX; Death domain associated protein, NR4A1; Nuclear receptor subfamily 4 group A member 1, CASP8AP2; Caspase 8 associated protein 2, SUMO1; Small ubiquitin like modifier 1, FADD; Fas associated via death domain, CASP8; Caspase 8, CASP6; Caspase 6, CASP7; Caspase 7, CFLAR; CASP8 and FADD like apoptosis regulator, MAPK8; Mitogen-activated protein kinase 8, MAPK14; Mitogen-activated protein kinase 14, MAP2K3; Mitogen-activated protein kinase kinase 3, MAP3K5; Mitogen-activated protein kinase kinase kinase 5, TRADD; TNFRSF1A associated via death domain, RIPK1; Receptor interacting serine/threonine kinase 1, PMT1; Protein O-mannosyltransferase-1, AKT1; AKT serine/threonine kinase 1, MOAP1; Modulator of apoptosis 1, PEX5; Peroxisomal biogenesis factor 5, CASP9; Caspase 9, SIVA1; SIVA1 apoptosis inducing factor

Fig. 6

TRIM21 regulates TP53-mediated apoptosis and inflammasome activation. TRIM21 activates the formation of mature CASP8 and CASP1 and activates the inflammasome. TRIM21 also activates BAX-BAK1-mediated mitochondrial membrane pore formation and SIVA1- and TP53-mediated ASC transcription. In C. elegans, TRIM21 induces ubiquitination of CED1 to form a cell corpse. TRIM21, tripartite motif containing 21, TP53; Tumor protein p53, CASP8, Caspase 8, CASP1; Caspase 1, CASP3; Caspase 3, CASP7; Caspase 7, BAX; BCL2 associated X, apoptosis regulator, BAK1; BCL2 antagonist/killer 1, SIVA1; SIVA1 apoptosis-inducing factor, ASC/CARD; Apoptosis-associated speck-like protein containing a caspase recruitment domain, C. elegans; Caenorhabditis elegans, CED1; Cell death abnormality protein 1, B2M; Beta-2-microglobulin, TRIM21; Tripartite motif containing 21, Ub; Ubiquitin, UBC21; Ubiquitin-conjugating enzyme 21, RBC; Red blood cell