Table 3.

Human diseases associated with defects in CMA

Disease subtype	CMA substrate	CMA activity	Observations	Refs
Cancer
Malignant transformation	CIP2A	Reduced	CMA regulates levels of MYC oncogene	114
	TCTP (acetylated)	Reduced	CMA regulates levels of TCTP	28
	MDM2	Reduced	CMA degrades the oncogene MDM2	115
	Unknown	Reduced	CMA is required for efficient exposure of ecto-CRT (eat me signal) in immunogenic cell death	116
Tumour survival and/or growth	Unknown	Increased	CMA required for Warburg effect	18
	PEA-15	n.d.	CMA degrades the anti-oncogenic variant	25
	PKM2	Increased	CMA required for Warburg effect	27
	BBC3a	Increased	CMA degrades this pro-apoptotic protein, reducing cancer cell apoptosis	110
Breast cancer	MST1 (de-acetylated)	Increased	CMA favours degradation of tumour suppressor MST1	30
	Oxidized proteins	Increased	CMA provides cancer cells chemoresistance and defence against ROS	101
	HSD17B4 (acetylated)	Increased	Failure to acetylate makes the protein resistant to CMA; favours cancer	102
Colorectal cancer	P300	Increased	CMA of acetyltransferase p300 confers 5-fluorouracil resistance	103
Gastric cancer	RND3	Increased	CMA degradation of RND3 sustains proliferation	26
Hepatocellular carcinoma	Unknown	Increased	LAMP2A blockage reduces cancer cell viability	104
	HMGB1	n.d.	CMA degrades HMGB1 to downregulate p53, and this confers resistance to irradiation-induced apoptosis	105
	Cyclin D1?	Increased	Macrophage-secreted IL-17 increases LAMP2A — proposed mechanism for oxaliplatin resistance	107b
	Unknown	Increased	Increased LAMP2A levels proposed to promote cancer cell survival in the cirrhotic liver	106b
Non-small-cell lung cancer	MCL1	n.d.	CMA stabilizes the prosurvival protein MCL1	111
	NCOR	n.d.	CMA degrades misfolded NCOR reducing ER stress	108
Myeloid leukaemia	AF1Qa	n.d.	CMA degrades the poor prognosis biomarker AF1Q	118
	Hexokinase II	n.d.	CMA depletes hexokinase and induces metabolic catastrophe upon blockage of macroautophagy	112
Neurodegenerative disorders
General neuronal degeneration	MEF2A	n.d.	CMA degradation of oxidized MEF2A protects primary neurons from oxidative stress	72
	MEF2Da	n.d.	CMA degradation of oxidized MEF2D protects primary neurons from oxidative stress	119
	Unknown	Reduced	Blocking CMA leads to dopaminergic neurodegeneration	90
	Unknown	n.d.	Inverse correlation between LAMP2A levels in brain regions and their susceptibility to protein aggregation	79b
Parkinson disease	α-Synuclein	Reduced	α-Synuclein is degraded by CMA but pathogenic α-synuclein blocks CMA	17,61,78,89
	α-Synuclein	Reduced	Blockage of LAMP2A in substantia nigra in rats leads to neurodegeneration	90
	LRRK2	Reduced	LRRK2 is degraded by CMA but pathogenic LRRK2 blocks CMA	81
	PARK7 (oxidized)	n.d.	CMA protects mitochondrial function by degrading nonfunctional PARK7	66
	UCHL1	Reduced	Pathogenic UCHL1 blocks CMA	82,83
	VPS35 mutant	Reduced	Pathogenic VPS35 impairs endosome-to-Golgi complex retrieval of LAMP2A and accelerates LAMP2A degradation	56
	GBA1 mutant	Reduced	GBA1 mutants prevent autophagy lysosomal reformation, affecting all forms of autophagy	93
	α-Synuclein mutant	n.d.	Nrf2 expression in astrocytes slows down CMA decline in PD mice	92
	Unknown	Increased	LAMP2A upregulation (AAV) protects PD neurons	91b
	Unknown	Reduced	Reduced levels of LAMP2A in PD patient brains	94b
	Unknown	Reduced	Reduced LAMP2A and HSC70 transcripts in PD brains due to increase of six miRNAs that control LAMP2A expression	97b
	α-Synuclein	Reduced	miRNA against HSC70 (miR-320a) reduces α-synuclein degradation	120b
	α-Synuclein	Reduced	Reduced LAMP2A protein in early stage PD brains (even before α-synuclein accumulation). CMA dysfunction is an early event	95b
	Unknown	Reduced	GBA-affected brain regions have reduced LAMP2A levels	95b
	Unknown	Reduced	Reduced LAMP2A or HSC70 mRNA and LAMP2A and HSC70 protein levels in leukocytes from PD patients	121b,122b
	Unknown	n.d.	Sequence variants and SNPs in the LAMP2 promoter in PD patients	96b
Prion diseases	Prion protein	Increased	Upregulation of LAMP2A and HSC70 (protective)	123b
Alzheimer disease	Tau	Decreased	Inefficient CMA	84
	APP c-term	n.d.	Eliminating KFERQ from APP leads to C-terminal fragment accumulation	98
Frontotemporal dementia	TDP-43	n.d.	CMA contributes to degradation of TDP-43	85
Huntington disease	Huntingtin	n.d.	CMA contributes to degradation of huntingtin	86–88
Heart diseases
Heart failure	Ryanodine R2 (oxidized)	Reduced	CMA removes oxidized ryanodine receptor type 2; inability to do so may lead to heart failure (hypothesis)	124
Danon disease	Unknown	Reduced	No LAMP2A, undegraded proteins attributed to low CMA	125b
Eye diseases
Leber congenital amaurosis	Unknown	Increased	Upregulation of total LAMP2 expression suggested to protect against early apoptotic events	126b
Liver diseases
Acute liver failure	Unknown	Reduced	Reduced LAMP2A levels	127b
NASH	Unknown	Reduced	Increased LAMP2A expression (compensatory)	128b
Hepatosteatosis	Unknown	Reduced	Reduced LAMP2A levels	129b
Alcoholic fatty liver	Unknown	Reduced	Reduced LAMP2A levels	130b
Lung diseases
Emphysema (cigarette smoke)	Unknown	Increased	CMA upregulated, protective against apoptosis	131
Kidney diseases
Diabetes	PAX2	Reduced	Reduced PAX2 CMA leads to kidney hypertrophy	132
Muscle diseases
Sporadic inclusion-body myositis	Unknown	Increased	LAMP2A mRNA and protein upregulated (likely in response to macroautophagy and proteasome decrease)	133b
Neuronal diseases
Spinal cord injury	ROS damaged proteins?	Increased	HDAC6 upregulates CMA (protective)	134
Brain ischaemia	No specific	Increased	CMA upregulation (protective)	58
Traumatic brain injury	Damaged proteins	Increased	LAMP2A levels increase during the recovery time (protective)	135b
Immune system
Immunosenescence	ITCH, RCAN1	Reduced	Failure to activate T cells because of reduced CMA; LAMP2A expression restores T cell response	21
Innate antiviral response	STING (desumoylated)	n.d.	CMA degrades STING in the late phase of infection to shut down the antiviral response	73
Salmonella	Unknown	Increased?	Recruits LAMP2A and HSC70 (CMA for nutrients?)	65
Lupus	Unknown	Increased	Increased LAMP2A expression	136b
Lysosomal storage disorders
Galactosialidosis	Unknown	Increased	Higher CMA by stabilizing LAMP2A	51
Cystinosis	Unknown	Reduced	Compromised LAMP2A trafficking to lysosomes	54,55
Mucolipidosis	Unknown	Reduced	Patient cells have lower CMA activity	137

APP, amyloid precursor protein; AAV, adeno-associated virus; BBC3, Bcl-2-binding component 3 (also known as PUMA); CIP2A, protein CIP2A (also known as KIAA1524); CMA, chaperone-mediated autophagy; ecto-CRT, surface-exposed calreticulin; ER, endoplasmic reticulum; GBA, glucocerebrosidase; HDAC6, histone deacetylase 6; HMGB1, high mobility group protein B1; HSC70, heat shock cognate 71 kDa protein (also known as HSPA8); HSD17B4, peroxisomal multifunctional enzyme type 2; IL-17, interleukin-17; ITCH, E3 ubiquitin-protein ligase Itchy homolog; LAMP2A, lysosome-associated membrane protein type 2A; LRRK2, leucine-rich repeat serine/threonine-protein kinase 2; MEF, myocyte-specific enhancer factor; miRNA, microRNA; MST1, mammalian Ste20-like kinase 1 (also known as STK4); MYC, MYC proto-oncogene protein; NASH, nonalcoholic steatohepatitis; n.d., not determined; NCOR, nuclear receptor corepressor; PD, Parkinson disease; PEA-15, 15 kDa phosphoprotein enriched in astrocytes (also known as PED); PARK7, protein/nucleic acid deglycase DJ-1; RCAN1, regulator of calcineurin 1; RND3, Rho-related GTP-binding protein RhoE; ROS, reactive oxygen species; SNPs, single nucleotide polymorphisms; STING, stimulator of interferon genes protein; Tau, tau protein; TCTP, translationally-controlled tumour protein; TDP-43, TAR DNA-binding protein 43; UCHL1, ubiquitin carboxyl-terminal hydrolase isozyme L1; VPS35, vacuolar protein sorting-associated protein 35.

^aIndicates no bona-fide KFERQ-like motif has been identified upon sequence analysis.

^bIndicates studies in which changes in CMA are proposed on the basis of LAMP2A level measurements but CMA activity has not yet been analysed.