Alternative titles; symbolsMICROTUBULE-ASSOCIATED PROTEINS 1A AND 1B, LIGHT CHAIN 3MAP1ALC3MAP1BLC3LC3ALC3HGNC Approved Gene Symbol: MAP1LC3ACytogenetic location...
Alternative titles; symbols
HGNC Approved Gene Symbol: MAP1LC3A
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:34,546,822-34,560,344 (from NCBI)
▼ Cloning and Expression
Microtubule-associated proteins MAP1A (600178) and MAP1B (157129) constitute nearly half of the mass of all the microtubule associated proteins that copurify with brain microtubules. MAP1A and MAP1B are each composed of a heavy chain and multiple light-chain subunits. Two of these light-chain subunits, LC1 and LC2, are encoded within the 3-prime end of the same open reading frames that encode the MAP1B and MAP1A heavy chains, respectively (Hammarback et al., 1991; Langkopf et al., 1992). Mann and Hammarback (1996) examined the expression of another light chain, LC3, which is a component of both MAP1A and MAP1B microtubule-binding complexes. They found that, although LC3 was expressed exclusively in cells expressing heavy chains, developmental changes in the total amount of LC3 protein were not proportional to the amounts of either heavy chain MAP1A or MAP1B. Using LC3-specific oligonucleotides, Mann and Hammarback (1996) amplified a 300-bp LC3 fragment from a human retina cDNA library.
By searching an EST database for sequences similar to rat Map1lc3, followed by PCR of a heart cDNA library, He et al. (2003) cloned MAP1LC3A. The deduced 121-amino acid protein shares 81% identity with rat Map1lc3. Northern blot analysis detected a 1.1-kb transcript in most tissues examined, with highest expression in heart, brain, liver, skeletal muscle, and testis. No MAP1LC3A expression was detected in thymus and peripheral blood leukocytes. Western blot analysis of transfected human embryonic kidney cells detected MAP1LC3A proteins of about 18 and 15 kD. Following fractionation of transfected HeLa cells, the 15-kD form associated with the membrane pellet and the 18-kD form associated with both the membrane and cytosolic fractions.
▼ Gene Function
Rat Lc3 is processed into cytosolic and membrane-bound forms termed Lc3 I and Lc3 II, respectively. Kabeya et al. (2000) found that the autophagic vacuole fraction prepared from starved rat liver was enriched with Lc3 II. Immunoelectron microscopy revealed specific labeling of autophagosome membrane in addition to cytoplasmic labeling. Lc3 II was present both inside and outside autophagosomes. Mutation analysis indicated that Lc3 I was formed by removal of the C-terminal 22 amino acids from newly synthesized Lc3, leaving a C-terminal glyc120 residue. A fraction of Lc3 I was then converted into Lc3 II. The amount of Lc3 II produced correlated with the extent of autophagosome formation.
He et al. (2003) found that MAP1LC3A underwent C-terminal cleavage, resulting in a protein with the conserved gly120 as its terminal residue. Gly120 was required for posttranslational modification of MAP1LC3A.
Behrends et al. (2010) reported a proteomic analysis of the autophagy interaction network (AIN) in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new AIN components have roles in vesicle trafficking, protein or lipid phosphorylation, and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The 6 human orthologs of yeast autophagy-8 (ATG8), MAP1LC3A, MAP1LC3B (609604), MAP1LC3C (609605), GABARAP (605125), GABARAPL1 (607420), and GABARAPL2 (607452), interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. Behrends et al. (2010) concluded that their studies provided a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.
Choy et al. (2012) found that the intracellular pathogen Legionella pneumophila could interfere with autophagy by using the bacterial effector protein RavZ to directly uncouple Atg8 proteins attached to phosphatidylethanolamine on autophagosome membranes. RavZ hydrolyzed the amide bond between the carboxyl-terminal glycine residue and an adjacent aromatic residue in Atg8 proteins, producing an Atg8 protein that could not be reconjugated by Atg7 (see 608760) and Atg3 (see 609606). Thus, Choy et al. (2012) concluded that intracellular pathogens can inhibit autophagy by irreversibly inactivating Atg8 proteins during infection.
Dou et al. (2015) reported that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1 (LMNB1; 150340), and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS (see 190020). Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevented activated RAS-induced lamin B1 loss and attenuated oncogene-induced senescence in primary human cells. Dou et al. (2015) concluded that this function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.
▼ Biochemical Features
Microtubule-associated protein light chain-3, a mammalian homolog of yeast Atg8, plays an essential role in autophagy, which is involved in the bulk degradation of cytoplasmic components by the lysosomal system. Sugawara et al. (2004) described the crystal structure of LC3 at 2.05-angstrom resolution; it has a ubiquitin fold at the C-terminal region and 2 helices at the N-terminal region.
Li et al. (2019) hypothesized that compounds that interact with both the autophagosome protein LC3 and the disease-causing mutant huntingtin protein (mHTT; 613004)m which contains an expanded polyglutamine (polyQ) tract, may target mHTT for autophagic clearance. Li et al. (2019) used small molecule microarray-based screening to identify 4 compounds that interact with both LC3 and mHTT, but not with the wildtype HTT protein. Some of these compounds targeted mHTT to autophagosomes, reduced mHTT levels in an allele-selective manner, and rescued disease-relevant phenotypes in cells and in vivo in fly and mouse models of Huntington disease. Li et al. (2019) further showed that these compounds interact with the expanded polyglutamine stretch and could also lower the level of mutant ataxin-3 (ATXN3; 607047), another disease-causing protein with an expanded polyglutamine tract. Li et al. (2019) concluded that their study presented candidate compounds for lowering mHTT and potentially other disease-causing proteins with polyglutamine expansions, demonstrating the concept of lowering levels of disease-causing proteins using autophagosome-tethering compounds.
Mann and Hammarback (1996) mapped the LC3 gene to chromosome 20cen-q13 using a human/rodent hybrid cell mapping panel.