Microtubule-associated proteins 1A/1B light chain 3B (hereafter referred to as LC3) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''MAP1LC3B''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
LC3 is a central protein in the autophagy pathway where it functions in
autophagy substrate selection and
autophagosome
An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, i ...
biogenesis
Spontaneous generation is a superseded scientific theory that held that living creatures could arise from nonliving matter and that such processes were commonplace and regular. It was hypothesized that certain forms, such as fleas, could arise ...
. LC3 is the most widely used marker of autophagosomes.
Discovery
LC3 was originally identified as a
microtubule associated protein in rat brain. However it was later found that the primary function of LC3 is in
autophagy, a process that involves the bulk degradation of cytoplasmic components.
The ATG8 protein family
MAP1LC3B is a member of the highly conserved
ATG8
Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for aut ...
protein family. ATG8 proteins are present in all known
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
organisms. The animal ATG8 family comprises three subfamilies: (i) microtubule-associated protein 1 light chain 3 (MAP1LC3); (ii) Golgi-associated ATPase enhancer of 16 kDa (GATE-16); and (iii) γ-amino-butyric acid receptor-associate protein (
GABARAP
Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the ''GABARAP'' gene.
Function
Gamma-aminobutyric acid A receptors ABA(A) receptorsare ligand-gated chloride channels that mediate inhibitory neurot ...
). ''MAP1LC3B'' is one of the four genes in the MAP1LC3 subfamily (others include ''
MAP1LC3A
Microtubule-associated proteins 1A/1B light chain 3A is a protein that in humans is encoded by the ''MAP1LC3A'' gene. Two transcript variants encoding different isoforms have been found for this gene.
Function
MAP1A and MAP1B are microtubule- ...
'', ''
MAP1LC3C'', and ''
MAP1LC3B2'').
Function
Cytoplasmic LC3
Newly synthesized LC3's C-terminus is hydrolyzed by a cysteine protease called
ATG4B
Cysteine protease ATG4B is an enzyme that in humans is encoded by the ''ATG4B'' gene.
Function
Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential ...
exposing Gly120, termed LC3-I. LC3-I, through a series of ubiquitin-like reactions involving enzymes
ATG7,
ATG3, and
ATG12
Autophagy related 12 is a protein that in humans is encoded by the ''ATG12'' gene.
Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autopha ...
-
ATG5
Autophagy related 5 (ATG5) is a protein that, in humans, is encoded by the ''ATG5'' gene located on Chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic ve ...
-
ATG16, becomes conjugated to the head group of the lipid
phosphatidylethanolamine
Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate- ethanolamine to diglycerides, releasing cytidine monophosphate. ''S''-Adenosyl methionine can ...
. The lipid modified form of LC3, referred to as LC3-II, is believed to be involved in autophagosome membrane expansion and fusion events. However, the exact role of LC3 in the autophagic pathway is still discussed, and the question of whether LC3 is required for autophagy is debated since knockdown of MAP1LC3B is compensated by the other members of the MAP1LC3 subfamily. Previous studies showed that MAP1LC3B knock out mice develop normally, possibly due to a then unknown compensatory mechanism. Further work, however, demonstrated that LC3 is required for autophagy by simultaneously down-regulating all of the MAP1LC3 subfamily members. While yet another study argues that MAP1LC3 knockdown does not affect bulk autophagy, whereas its
GABARAP
Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the ''GABARAP'' gene.
Function
Gamma-aminobutyric acid A receptors ABA(A) receptorsare ligand-gated chloride channels that mediate inhibitory neurot ...
family members are crucial for the process.
LC3 also functions—together with autophagy receptors (e.g.
SQSTM1)--in the selective capture of cargo for autophagic degradation. Independent of autophagosomes, a single soluble LC3 is associated with an approximately 500 kDa complex in the cytoplasm.
Nuclear LC3
The importance of the nuclear functions of autophagy proteins should not be underestimated. A large pool of LC3 is present in the nucleus of a variety of different cell types. In response to starvation, nuclear LC3 is deacetylated and trafficked out of the nucleus into the cytoplasm where it functions in autophagy. Nuclear LC3 interacts with
lamin B1
Lamin-B1 is a protein that in humans is encoded by the ''LMNB1'' gene.
The nuclear lamina consists of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly ...
, and participates in the degradation of
nuclear lamina
The nuclear lamina is a dense (~30 to 100 nm thick) fibrillar network inside the nucleus of eukaryote cells. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina ...
. LC3 is also enriched in
nucleoli
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of s ...
via its triple arginine motif, and associates with a number of different nuclear and nucleolar constituents including:
MAP1B
Microtubule-associated protein 1B is a protein that in humans is encoded by the ''MAP1B'' gene.
Function
This gene encodes a protein that belongs to the microtubule-associated protein family. The proteins of this family are thought to be invol ...
,
tubulin
Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
, and several
ribosomal protein
A ribosomal protein (r-protein or rProtein) is any of the proteins that, in conjunction with rRNA, make up the ribosomal subunits involved in the cellular process of translation. ''E. coli'', other bacteria and Archaea have a 30S small subunit an ...
s.
Structure
LC3 shares structural homology with
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
, and therefore has been termed a
ubiquitin-like protein
Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class ...
.
LC3 has a LDS (LIR docking site)/hydrophobic binding interface in the N terminus which interacts with LIR (LC3 Interacting Region) containing proteins.
This domain is rich in hydrophobic amino acids, the mutation of which impairs the ability of LC3 binding with LIR containing proteins, many of which are autophagy cargo adapter proteins. For example, sequestosome (SQSTM1) interacts with Phe 52 and Leu53 aminoacids present in hydrophobic binding interface of LC3 and any mutation of these amino acids prevents LC3 interaction with SQSTM1.
Post-translational regulation
References
Further reading
*
*
*
*
*
*
*
*
*
External links
*
{{PDB Gallery, geneid=81631