Multifaceted Roles of Autophagy in Health and Disease

Autophagy is a fundamental cellular process that allows cells to remove and recycle damaged proteins and organelles. ^2,3 There are 3 forms of autophagy: macroautophagy, in which an autophagosome forms around cytoplasmic material and/or organelles and subsequently fuses with the lysosome for degradation; microautophagy, in which lysosomes invaginate for uptake of cytoplasmic materials; and chaperone-mediated autophagy. Macroautophagy (henceforth referred to as autophagy) is considered the principle form of autophagy and is critical for cellular homeostasis under both basal and stressed conditions. ² The importance of basal autophagy is evidenced by the perinatal mortality of mice deficient in autophagy-related proteins. ² Under stressed conditions, autophagy can be induced and functions as a key pathway to remove damaged organelles, such as mitochondria, or aggregated proteins. In the face of starvation or nutrient deprivation, autophagy is induced to recycle intracellular macromolecules, providing cells with essential building blocks and energy sources to maintain their basic functions. ^2,7 As a key homeostatic mechanism, a strict balance of autophagy is necessary, as too much or too little autophagy can be detrimental to the cell and therefore detrimental to the organism. ³

Considering its central role in cellular homeostasis, it is not surprising that autophagy has been incriminated in a wide range of disease processes and pathogeneses. Insufficient or defective autophagy has been implicated in the pathogenesis of many neurodegenerative diseases. ⁵ For instance, reduced autophagic clearance of damaged mitochondria has been shown to be important in the pathogenesis of Parkinson’s disease, ⁴ and defects in autophagy and lysosomal clearance have been suggested to play a significant role in Alzheimer’s disease. ⁵ In veterinary medicine, changes in autophagy have recently been associated with degenerative myelopathy in Pembroke Welsh Corgis ⁶ and progressive neurologic disease of Lagotto Romagnolo dogs. ⁸ Specifically, Ogawa et al ⁶ have demonstrated that Pembroke Welsh Corgis with degenerative myelopathy have increased accumulation of the autophagosome-associated protein LC3 in neurites and the autophagosome adaptor protein p62 in the neuropil of affected spinal cords. Accumulations of these proteins were associated with reduced expression of Beclin1 and Atg16 L, both of which play roles in autophagosome isolation membrane formation, collectively suggesting that affected animals may have disruptions in autophagy pathways. ⁶ Mutations in the autophagy-related gene ATG4D have been identified in Lagotto Romagnolo dogs with progressive neurodegenerative disease and have been associated with altered basal autophagy. ⁸ In cancer, autophagy plays complex and context-specific roles. During tumor initiation, autophagy can prevent neoplastic transformation by removing damaged proteins, DNA, or organelles and by reducing oxidative damage. However, during cancer progression, autophagy can be protect transformed cells by allowing them to adapt to cell stresses associated with rapid proliferation, nutrient poor environments, or chemotherapies. ⁷

In the immune system, autophagy and autophagy-related proteins have complex and multifaceted roles. In this issue of Veterinary Pathology, Kinsella et al ¹ describe the current knowledge of autophagy in the immune system and host defense. Autophagy-related proteins have been shown to play roles in the development of the immune system, innate pathogen recognition and inflammatory responses, antigen presentation, and pathogen clearance. In addition, polymorphisms in autophagy-related genes have been associated with autoimmune and inflammatory diseases, with the most notable association being ATG16L1 polymorphisms and Crohn’s disease. ¹ The diverse roles of autophagy in the immune system highlight the fundamental importance of this pathway in both health and disease and the complexity of interactions between autophagy and other cellular processes.

The pleiotropic roles of autophagy-related proteins in the immune system make this an exciting target to modulate immune responses, both in the face of autoinflammatory diseases and in response to pathogenic infections. However, as Kinsella et al ¹ point out, since some proteins involved in autophagy pathways may play other cellular roles, it will be important to determine direct autophagy versus nonautophagy roles in immune function to determine the best way to modulate these proteins and to mitigate unintended therapeutic consequences. In addition, as a major pathway for cellular homeostasis, the appropriate balance of autophagy within a cell or tissue becomes a critical consideration. Too much autophagy can result in cell death, whereas inadequate autophagy can allow for the accumulation of misfolded proteins and damaged organelles, inadequate immune response, and possible cellular transformation. Furthermore, the appropriate direction for pathway modulation may be extremely context dependent. This context-dependent nature of autophagy is highlighted in the biphasic role of autophagy in carcinogenesis and tumor progression. ⁷ Although the dynamics and interactions of the autophagy pathway are complex, the broad and essential functions of autophagy in health and disease make it an equally essential pathway to investigate, understand, and potentially modulate.