Novel Insights into The Roles of N6-methyladenosine (m6A) Modification and Autophagy in Human Diseases

Abstract

Autophagy is an evolutionarily conserved cellular degradation and recycling process. It is important for maintaining vital cellular function and metabolism. Abnormal autophagy activity can cause the development of various diseases. N⁶-methyladenosine (m⁶A) methylation is the most prevalent and abundant internal modification in eukaryotes, affecting almost all aspects of RNA metabolism. The process of m⁶A modification is dynamic and adjustable. Its regulation depends on the regulation of m⁶A methyltransferases, m⁶A demethylases, and m⁶A binding proteins. m⁶A methylation and autophagy are two crucial and independent cellular events. Recent studies have shown that m⁶A modification mediates the transcriptional and post-transcriptional regulation of autophagy-related genes, affecting autophagy regulatory networks in multiple diseases. However, the regulatory effects of m⁶A regulators on autophagy in human diseases are not adequately acknowledged. In the present review, we summarized the latest knowledge of m⁶A modification in autophagy and elucidated the molecular regulatory mechanisms underlying m⁶A modification in autophagy regulatory networks. Moreover, we discuss the potentiality of m⁶A regulators serving as promising predictive biomarkers for human disease diagnosis and targets for therapy. This review will increase our understanding of the relationship between m⁶A methylation and autophagy, and provide novel insights to specifically target m⁶A modification in autophagy-associated therapeutic strategies.

Keywords: Autophagy; Biomarkers; N6-methyladenosine (m6A); RNA modification; Therapeutic targets.

Figure 1

The biological functions of m⁶A regulators. m⁶A modifying enzymes include writers, erasers and readers. Writers (METTL3, METTL14, WTAP, KIAA1429, METTL16, etc.) can add a methyl group to different types of RNA. Erasers (ALKBH5 and FTO) can eliminate this modification. Readers (the YTH family, IGF2BP1, and hnRNPA2B1) could identify the m⁶A modification sites and regulate the downstream functional activities.

Figure 2

The mechanism of the YTH family proteins. In proteins containing the YTH domain, YTHDF2 promotes the decay of mRNA by recruiting the CCR4-NOT complex. YTHDF3 also helps mRNA decay. YTHDC2 and YTHDF1 can regulate the translation of mRNA. YTHDC1 can selectively splice pre-mRNA into mature transcripts and mediate the nuclear output of mature mRNA. Meanwhile, YTHDC1 can improve the stability of mRNA as well as YTHDF1.

Figure 3

Molecular mechanisms of autophagy process. Autophagy initiation begins with the activation of the ULK1 complex under the control of AMPK and mTORC1. Induction of the ULK1 complex transfers the PI3K class III complex from the cytoplasm to the pre-autophagosomal structure, thereby promoting phagophore formation. The phagophore continues to expand, close, and form autophagosomes through the action of two ubiquitin-like conjugation systems: (1) the ATG12 system and (2) the LC3 system. Subsequently, the outer membrane of the autophagosome fuses with the lysosomal membrane to form autolysosomes where the cargo degradation occurs. UVRAG, RAB7A, and LAMP2 mediate autophagosome maturation and fusion with lysosomes. AMPK, 5' adenosine monophosphate-activated protein kinase; ULK1, Unc-51 Like Autophagy Activating Kinase 1; FIP200: Family interacting protein 200Kd; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; ATG, Autophagy related gene; LC3, Microtubule-associated protein 1A/1B-light chain 3; UVRAG, UV radiation resistance-associated gene protein; RAB7A, Ras-related protein Rab-7a; LAMP2, lysosomal-associated membrane protein 2.

Figure 4

Regulatory effects of m⁶A methyltransferases on autophagy in human diseases. m⁶A methyltransferases play an important role in nasopharyngeal carcinoma, CML, seminoma, NSCLC, HCC, PC, OSCC, H/R damage, airway epithelial cells injury, TMJ OA, Leydig cells damage, and podocytopathies, by targeting ZFAS1, PTEN, FOXO3, eIF4G1, LKB1, ULK1, TFEB, OSGIN1, Bcl2/Beclin1, CAMKK2, PPM1A, and SIRT1. The underlying mechanisms involve the activation of the PI3K/AKT pathway, AMPK and ATGs' activation. CML: chronic myeloid leukemia; NSCLC: non-small cell lung cancer; HCC: hepatocellular carcinoma; PC: pancreatic carcinoma; OSCC: oral squamous cell carcinoma; H/R: hypoxia/reoxygenation; TMJ OA: temporomandibular joint osteoarthritis.

Figure 5

Regulatory effect of m⁶A demethylases on autophagy in human diseases. m⁶A demethylases play an important role in EOC, ccRCC, skin tumor, GC, OSCC, NSCLC, endometriosis, TMJ OA, Leydig cells damage, IVD, and H/R damage, by targeting circ RAB11FIP1, SIK2, eIF4G1, ULK1, UBE2C, HuR, TFEB, FIP200, CAMKK2, and PPM1A. The underlying mechanisms involve the activation of AMPK and ATGs. EOC: epithelial ovarian cancer; ccRCC: clear cell renal cell carcinoma; GC: gastric carcinoma; OSCC: oral squamous cell carcinoma; NSCLC: non-small cell lung cancer; IVD: intervertebral disc degeneration; H/R: hypoxia/reoxygenation.

Figure 6

Regulatory effect of m⁶A binding protein on autophagy in human diseases. m⁶A binding protein play an important role in HCC, diabetes, hair cell injury, and H/R damage, by targeting circ MDK, ELAVL1, TFEB, and SQSTM1. The underlying mechanisms involve the activation of ATGs. HCC: hepatocellular carcinoma; H/R: hypoxia/reoxygenation.

Figure 7

Potential therapeutic value of m⁶A modification in regulating autophagy. m⁶A modification plays a key role in many aspects of disease treatment. m⁶Aregulators can become a potential target for therapy by affecting (1) the progression of tumor and non-tumor diseases, (2) the sensitivity of tumor cells to various chemotherapeutic drugs, (3) the response of cells to H/R damage, and (4) the damage of environmental pollutants.