CLEC16A-An Emerging Master Regulator of Autoimmunity and Neurodegeneration

Abstract

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms involved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with CLEC16A risk variants. Accordingly, interventions directed at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective therapy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the CLEC16A gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this information is being translated into practical and effective applications in the clinic.

Keywords: C-type lectin-like domain family 16A (CLEC16A) gene; CLEC16A; Parkinson’s disease (PD); autoimmunity; autophagy; genome-wide association studies (GWAS); mitophagy; neurodegeneration; suppressor of cytokine signaling 1 (SOCS1); susceptibility loci; type 1 diabetes (T1D).

Figure 1

Schematic depicting the chromosome16p13 genetic region comprising CIITA (Class II Major Histocompatibility Complex Transactivator), DEXI (homolog, cytotoxic suppression), CLEC16A (C-type lectin domain family 16, member A), SOCS1 (Suppressor of Cytokine Signaling 1), and RMI2 (RecQ Mediated Genome Instability 2). (Genome Reference Consortium Human Build 38 (GRCh38), chromosome 16: 10.971.055–11.349.335).

Figure 2

CLEC16A disease association timeline. CLEC16A association with 18 diseases described to date: T1D was the first disease to show genome-wide association (GWA) with CLEC16A, in 2007, followed by MS. Parkinson’s disease is the latest disease to be associated with CLEC16A, reported in 2021.

Figure 3

The 18 autoimmune disease-associated single nucleotide polymorphisms (SNPs) and their localization are depicted on the 238 kb CLEC16A gene. The chromosome 16p13.13 locus ~530 kb long region is the house of four genes (CIITA-DEXI-CLEC16A-SOCS1). CLEC16A is flanked by two neighboring genes: CIITA, which is required for the expression of MHC Class II, and SOCS1, a negative modulator of cytokine signaling. Primary adrenal insufficiency (PAI), allergic rhinitis (AR), alopecia areata (AA), asthma, autoimmune thyroid diseases (ATD), Celiac disease, common variable immunodeficiency (CVID), Crohn’s disease (CD), eosinophilic esophagitis (EE), juvenile idiopathic arthritis (JIA), multiple sclerosis (MS), Parkinson’s disease (PD), primary biliary cirrhosis (PBC), rheumatoid arthritis (RA), selective IgA deficiency, systemic lupus erythematosus (SLE), systemic sclerosis, and type 1 diabetes (T1D).

Figure 4

CLEC16A functions in autophagy. Autophagy comprises initiation, membrane nucleation, phagophore formation, phagophore expansion, fusion with the lysosome, degradation, and recycling. Initiation: Autophagy is initiated by the formation of a phagophore, a double-membraned structure that forms around the targeted cellular component. Once the phagophore is formed, it elongates and expands, forming the autophagosome. This process is mediated by the ATG12-ATG5-ATG16L complex and the LC3 protein, which is then lipidated and inserted into the growing autophagosome membrane. Maturation: The autophagosome then fuses with a lysosome, forming an autolysosome. The lysosome contains digestive enzymes that break down the contents of the autophagosome, allowing for the recycling of cellular components. Degradation: The degraded components are then released back into the cytoplasm for reuse by the cell. AMPK, mTOR, and ULK complex are all involved in the regulation of autophagy. AMPK (AMP-activated protein kinase) is a key energy-sensing enzyme that is activated in response to energy depletion. Activated AMPK stimulates autophagy by phosphorylating and activating ULK1, a protein involved in the initiation of autophagy. Autophagy induction is known to be inhibited by CLEC16A. Under starvation, CLEC16A clusters in the Golgi to interact with an unidentified mediator that would activate the mTORC1 complex fully once nutrients are available. It is speculated that CLEC16A regulates mTOR by controlling the stability and/or degradation of Rheb, which requires further investigation.

Figure 5

CLEC16A function in mitophagy. Mitophagy is a form of selective autophagy that targets damaged mitochondria for degradation via either the Parkin-dependent or Parkin-independent pathways. Autophagy receptors (P62, NBR1, NDP52, OPT), Ubiquitin, and ubiquitin-binding proteins are involved in the Parkin/PINK1-dependent mitophagy. Parkin-independent mitophagy involves the use of multiple mitophagy receptors (BNIP3, Nix/BNIP3L, FUNDC1, BCL2L13, and FKBP8) to target damaged mitochondria to the LC3-mediated autophagy machinery for clearance. The schematic depicts Parkin/PINK1-dependent mitophagy. AMPK, mTOR, and ULK complexes are also involved in the regulation of mitophagy. The normal mitophagy process comprises mitophagy initiation, membrane nucleation, phagophore formation, recognition of damaged mitochondria, phagophore expansion to form mature mitophagosome, fusion with the lysosome, and degradation (1). CLEC16A hypofunction leads to dysregulated autophagy and the accumulation of unhealthy mitochondria (2). Maintenance of the CLEC16A-NRDP1-USP8 mitophagy complex is crucial for promoting optimal cellular respiration and insulin secretion. Dysregulated mitophagy can lead to a buildup of damaged mitochondria and an increase in oxidative stress, ultimately leading to β-cell dysfunction and death. Similarly, in neurodegenerative diseases such as Parkinson’s, dysregulated mitophagy can lead to an accumulation of damaged mitochondria and impaired energy metabolism in neurons. This can contribute to neuronal dysfunction and death, as well as the accumulation of toxic protein aggregates that are characteristic of these diseases.

Figure 6

The multifaceted role of CLEC16A in receptor recycling in NK cells is illustrated in a schematic diagram, emphasizing the delicate balance required for NK cell function and homeostasis. The amount of CLEC16A protein is critical for maintaining this balance, as illustrated. In the left panel (1), the normal level of endogenous CLEC16A (yellow triangle) is shown to regulate receptor trafficking by participating in endosome recycling. CLEC16A binds to the Hrs/Actinin-4/BERP/Myosin V (CART) complex, facilitating the transport of receptor-enriched endosomes to the cell surface membrane. The amount of CLEC16A protein serves as a checkpoint for NK cells. Overexpression of CLEC16A (purple triangle, middle panel, 2) leads to its own ubiquitination, resulting in increased association with the CART complex, thereby disrupting efficient receptor recycling. Consequently, receptors are targeted for degradation through autophagy, leading to attenuated receptor signaling. Loss of CLEC16A (right panel, 3) leads to disrupted mitophagy and the accumulation of unhealthy mitochondria. CLEC16A stabilizes and prevents the proteasomal degradation of Nrdp1, which limits the recruitment of Parkin to the mitochondrial surface and promotes autophagosome-lysosome fusion during the late stages of mitophagy.

Figure 7

A hypothetical model for CLEC16A hypofunction and rescue by mitophagy/autophagy modulation. CLEC16A hypofunction leads to a vicious cycle of mitophagy/autophagy impairment and sustained ER stress. To restore cellular homeostasis in response to mitochondrial dysfunction mTOR, AMPK, and SIRT1 UPR-ER stress pathways, SOCS-mediated JAK-STAT signaling, apoptosis, and necro-apoptosis pathways can be targeted.