LC3C (MAP1LC3C) is a member of the microtubule-associated protein 1 light chain 3 (MAP1LC3) family, which also includes LC3A, LC3B, and LC3B2. LC3C is a core [autophagy](/entities/autophagy) protein involved in the formation and maturation of autophagosomes, playing crucial roles in cellular homeostasis and protein quality control. Dysregulation of LC3C and the autophagy pathway has been implicated in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [1].
Structure
Domain Architecture
LC3C contains several key structural features:
N-terminal region: Contains the ubiquitin-like fold domain that undergoes lipidation
LIR (LC3-interacting region) docking site: Critical for binding to autophagy receptors
C-terminal region: Contains the conserved glycine residue required for lipidation
Post-Translational Modifications
LC3C undergoes several important post-translational modifications:
Phosphorylation: LC3C can be phosphorylated at Ser12 and Ser24 by various kinases
Lipidation: The conjugation of phosphatidylethanolamine (PE) to the C-terminal glycine creates LC3C-II, the membrane-bound form
Acetylation: Regulates LC3C's autophagic function in response to cellular stress
Normal Function
Role in Autophagy
LC3C is essential for autophagosome formation and serves multiple functions:
Autophagosome nucleation: LC3C contributes to the recruitment of autophagy-related proteins to the phagophore
Membrane expansion: Facilitates the expansion of the autophagosomal membrane
Cargo recognition: Through LIR-mediated interactions, LC3C binds to autophagy receptors containing LIR motifs
Selective autophagy: LC3C has specialized roles in selective autophagy pathways, including mitophagy and xenophagy [2]
Expression in the Nervous System
In the central nervous system, LC3C is expressed in:
[Neurons](/entities/neurons) (particularly in cortical and hippocampal regions)
In AD, LC3C dysfunction contributes to disease pathogenesis through:
Impaired autophagic-lysosomal pathway: Reduced LC3C lipidation and autophagosome formation leads to accumulation of [amyloid-beta](/proteins/amyloid-beta) and [tau](/proteins/tau) aggregates
Defective mitophagy: Impaired clearance of damaged mitochondria contributes to neuronal energy deficits and oxidative stress
Synaptic dysfunction: Altered LC3C function affects synaptic protein turnover and plasticity [3]