Autophagy in Rheumatic Diseases: Role in the Pathogenesis and Therapeutic Approaches

Abstract

Autophagy is a lysosomal pathway for the degradation of damaged proteins and intracellular components that promotes cell survival under specific conditions. Apoptosis is, in contrast, a critical programmed cell death mechanism, and the relationship between these two processes influences cell fate. Recent evidence suggests that autophagy and apoptosis are involved in the self-tolerance promotion and in the regulatory mechanisms contributing to disease susceptibility and immune regulation in rheumatic diseases. The aim of this review is to discuss how the balance between autophagy and apoptosis may be dysregulated in multiple rheumatic diseases and to dissect the role of autophagy in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. Furthermore, to discuss the potential capacity of currently used disease-modifying antirheumatic drugs (DMARDs) to target and modulate autophagic processes.

Keywords: apoptosis; autophagy; rheumatic diseases.

Figure 1

The figure shows the principal steps of the autophagy process: induction, elongation and completion, lysosome fusion, and cargo degradation. Mammalian target of rapamycin (mTOR) plays a pivotal role in the inhibition of autophagy phosphorylating Atg13 and preventing its association with Atg1, which is critical for autophagosome formation. When cell growth and protein synthesis are scarce, mTOR is inactivated, and autophagy is induced as a compensatory mechanism. Rapamycin is also a potent mTOR inhibitor. Autophagosome formation requires two ubiquitin-like systems: the ATG12 conjugation system and the ATG8 (LC3) conjugation system. Atg5 is covalently conjugated to Atg12, facilitated by Atg7. The Atg12–Atg5 dimer then binds Atg16L, forming a multiprotein complex, which is recruited to the forming autophagosome’s isolation membrane through Atg16L. In the second conjugation system, Atg7 and Atg3 mediate the conjugation of LC3 to the lipid phosphatidylethanolamine (PE). LC3II, the membrane-bound, autophagosome-associated form, is required for membrane expansion. The last step is autophagosome–lysosome fusion to generate autolysosomes that degrade the cargo.