Target acquired: Selective autophagy in cardiometabolic disease

Abstract

The accumulation of damaged or excess proteins and organelles is a defining feature of metabolic disease in nearly every tissue. Thus, a central challenge in maintaining metabolic homeostasis is the identification, sequestration, and degradation of these cellular components, including protein aggregates, mitochondria, peroxisomes, inflammasomes, and lipid droplets. A primary route through which this challenge is met is selective autophagy, the targeting of specific cellular cargo for autophagic compartmentalization and lysosomal degradation. In addition to its roles in degradation, selective autophagy is emerging as an integral component of inflammatory and metabolic signaling cascades. In this Review, we focus on emerging evidence and key questions about the role of selective autophagy in the cell biology and pathophysiology of metabolic diseases such as obesity, diabetes, atherosclerosis, and steatohepatitis. Essential players in these processes are the selective autophagy receptors, defined broadly as adapter proteins that both recognize cargo and target it to the autophagosome. Additional domains within these receptors may allow integration of information about autophagic flux with critical regulators of cellular metabolism and inflammation. Details regarding the precise receptors involved, such as p62 and NBR1, and their predominant interacting partners are just beginning to be defined. Overall, we anticipate that the continued study of selective autophagy will prove to be informative in understanding the pathogenesis of metabolic diseases and to provide previously unrecognized therapeutic targets.

Figure 1. Accumulation of Dysfunctional Organelles in Cardiometabolic Disease

Organelle accumulation and dysfunction is a common feature of cardiometabolic diseases in nearly every tissue and cell type including hepatocytes, macrophages, myocytes, cardiomyocytes, pancreatic islet β-cells, and adipocytes. Specific players include lipid accumulation, mitochondrial dysfunction, protein aggregation, inflammasome activation, and peroxisome dysfunction.

Figure 2. Selective Autophagy Degrades Dysfunctional or Excess Organelles

In cardiometabolic disease states, dysfunctional and/or excess organelles produce adverse signals that mediate disease pathology. Mitochondria and peroxisomes produce reactive oxygen species, and mitochondria additionally release mitochondrial DNA (mtDNA) and incompletely oxidized lipid intermediates. Activated inflammasomes produce massive amounts of IL-1β. Lipid droplets are a relatively safe storage site for neutral lipids; their saturation results in lipotoxicity, ectopic lipid deposition, and membrane disruption. Protein aggregates are both inherently cytotoxic (proteotoxicity) and can activate inflammasomes as an example of pathological intraorganelle crosstalk (Bottom). Selective autophagy is a primary mode of degradation for each of these types of organelles and serves to both maintain intrinsic organelle function and limit toxic byproducts. Archetypal steps in selective autophagy include tagging of dysfunctional or excess cargo (for example, by ubiquitin), recognition by selective autophagy receptors (e.g. p62), delivery to the autophagosome, and fusion with the lysosome for complete degradation (Top).

Figure 3. Models of Key Molecular Events Mediating Pexophagy, Aggrephagy, and Inflammasomophagy

A. Pexophagy: Mammalian pexophagy primarily proceeds through Pex2-mediated ubiquitination of Pex5. NBR1 serves as the main selective autophagy receptor for peroxisomes that mediates interaction with the autophagosome. B. Aggrephagy: CHIP and Parkin are the main E3 ubiquitin ligases that target protein aggregates and inclusions. NBR1, p62, and ALFY interact with the autophagosome to mediate aggrephagy. C. Inflammasomophagy: Inflammasomes are targeted for autophagic destruction through at least two routes. A mechanism termed “precision” autophagy involves direct recognition of multiple inflammasome components by TRIM20 (also known as MEFV) which recruits key components of autophagy machinery such as Beclin, ULK1, and ATG8 (top). Alternatively, upon polyubiquitination of the ASC subunit by a yet to be identified E3 ligase, the inflammasome is recognized by p62 for autophagy (bottom).

Figure 4. Model of Key Molecular Events That Mediate Mitophagy

Mitophagy likely proceeds through several complementary mechanisms. Left: In response to mitochondrial damage, PINK1 phosphorylates ubiquitin to directly enhance NDP52 and OPTN binding. NDP52 and OPTN recruit several components of the autophagy machinery including ULK1 to initiate mitophagy. Bottom: PINK1 also activates the E3 ubiquitin ligase Parkin, which targets many mitochondrial proteins. The deubiquitinase USP30 opposes Parkin to spare lessdamaged mitochondria. Selective autophagy receptors for mitophagy include NDP52, OPTN, and p62. Right: BNIP3 family proteins in the mitochondrial outer membrane directly mediate mitophagy by binding to LC3. Center: Polyubiquitin/p62 oligomers cluster damaged mitochondria to favor mitophagy.

Figure 5. Molecular Mediators of Lipophagy

Left: Autophagosome recruitment to lipid droplets and downstream autophagosome-lysosome interaction depends on the activity of the small GTPase Rab7. Center: The neutral lipases ATGL and HSL contain LC3 binding domains that are required for recruitment to the lipid droplet, constituting a mechanism for crosstalk between lipophagy and neutral lipolysis. Right: PLIN2 and PLIN3 (PLIN2/3) proteins coat the lipid droplet surface and block both lipophagy and neutral lipolysis. Chaperone-mediated autophagy targets PLIN2/3 using HSC70 as an adapter, resulting in their direct translocation into lysosomes for degradation. This allows the machineries of both neutral lipolysis and lipophagy to access the lipid droplet.

Figure 6. Transcriptional Feedback Control of Selective Autophagy

Several parallel feedback loops couple sensing of organelle damage with transcriptional regulation of selective autophagy genes. Under basal conditions, KEAP1 binds to and targets NRF2 for proteasomal degradation. Protein aggregates and dysfunctional mitochondria accumulate p62, which binds to and sequesters KEAP1 to free NRF2 and activate its transcriptional activity. NRF2 targets many selective autophagy genes to degrade p62-tagged cargo. Similarly, TFEB translocates to the nucleus in response to mitochondrial and lysosomal stresses to transcribe selective autophagy, mitochondrial, and lysosomal genes.