LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles

Abstract

LAMP2 (lysosomal associated membrane protein 2) is one of the major protein components of the lysosomal membrane. There currently exist three LAMP2 isoforms, LAMP2A, LAMP2B and LAMP2C, and they vary in distribution and function. LAMP2A serves as a receptor and channel for transporting cytosolic proteins in a process called chaperone-mediated autophagy (CMA). LAMP2B is required for autophagosome-lysosome fusion in cardiomyocytes and is one of the components of exosome membranes. LAMP2C is primarily implicated in a novel type of autophagy in which nucleic acids are taken up into lysosomes for degradation. In this review, the current evidence for the function of each LAMP2 isoform in various pathophysiological processes and human diseases, as well as their possible mechanisms, are comprehensively summarized. We discuss the evolutionary patterns of the three isoforms in vertebrates and provide technical guidance on investigating these isoforms. We are also concerned with the newly arising questions in this particular research area that remain unanswered. Advances in the functions of the three LAMP2 isoforms will uncover new links between lysosomal dysfunction, autophagy and human diseases.Abbreviation: ACSL4: acyl-CoA synthetase long-chain family member 4; AD: Alzheimer disease; Ag: antigens; APP: amyloid beta precursor protein; ATG14: autophagy related 14; AVSF: autophagic vacuoles with unique sarcolemmal features; BBC3/PUMA: BCL2 binding component 3; CCD: C-terminal coiled coil domain; CMA: chaperone-mediated autophagy; CVDs: cardiovascular diseases; DDIT4/REDD1: DNA damage inducible transcript 4; ECs: endothelial cells; ER: endoplasmic reticulum; ESCs: embryonic stem cells; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA/β-glucocerebrosidase: glucosylceramidase beta; GSCs: glioblastoma stem cells; HCC: hepatocellular carcinoma; HD: Huntington disease; HSCs: hematopoietic stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IL3: interleukin 3; IR: ischemia-reperfusion; LAMP2: lysosomal associated membrane protein 2; LDs: lipid droplets; LRRK2: leucine rich repeat kinase 2; MA: macroautophagy; MHC: major histocompatibility complex; MST1: macrophage stimulating 1; NAFLD: nonalcoholic fatty liver disease; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NLRP3: NLR family pyrin domain containing 3; PARK7: Parkinsonism associated deglycase; PD: Parkinson disease; PEA15/PED: proliferation and apoptosis adaptor protein 15; PKM/PKM2: pyruvate kinase M1/2; RA: rheumatoid arthritis; RARA: retinoic acid receptor alpha; RCAN1: regulator of calcineurin 1; RCC: renal cell carcinoma; RDA: RNautophagy and DNautophagy; RNAi: RNA interference; RND3: Rho Family GTPase 3; SG-NOS3/eNOS: deleterious glutathionylated NOS3; SLE: systemic lupus erythematosus; TAMs: tumor-associated macrophages; TME: tumor microenvironment; UCHL1: ubiquitin C-terminal hydrolase L1; VAMP8: vesicle associated membrane protein 8.

Keywords: LAMP2A; LAMP2B; LAMP2C; autophagy; chaperone-mediated autophagy; lysosome.

Figure 1.

Schematic drawing of the structure of human LAMP2. The human LAMP2 gene has nine exons. Alternative splicing of pre-LAMP2 mRNA produces three isoforms: LAMP2A, LAMP2B and LAMP2C. The three isoforms have identical lumenal domains (aa 1 to aa 374, red) at the N terminus but distinct transmembrane (TD, aa 375 to aa 398, green) and C-terminal cytoplasmic domains (CCD, aa 399 or aa 340 to the C terminus for humans, blue).

Figure 2.

The role of three LAMP2 isoforms in autophagy. LAMP2A serves as a receptor and channel for transporting cytosolic proteins in a process called chaperone-mediated autophagy (CMA). LAMP2B regulates human cardiomyocyte function by mediating autophagosome-lysosome fusion by interacting with ATG14 and VAMP8 through its C-terminal coiled coil domain (CCD). LAMP2C mediates a novel type of autophagy targeting RNA or DNA for lysosomal degradation, termed RNautophagy and DNautophagy, respectively.

Figure 3.

Sequence variability within different functional domains of the three LAMP2 isoforms in vertebrate from six species. The amino acid sequence of the lumenal domains, transmembrane domain (TD) and C-terminal cytoplasmic domains (CCD) of LAMP2A, LAMP2B and LAMP2C. The GYXXX motif (green) located at the CCD are required for targeting LAMP2 to the lysosomal membrane, with GYEQF, GYQTL and GYQSV present at the C terminus of LAMP2A, LAMP2B and LAMP2C, respectively. The GYXXX motif (green) located at the CCD are required for targeting LAMP2 to the lysosomal membrane. Another motif GXXXXXXG, situated within the CCD, encompasses positively charged residues (red) which play crucial roles in binding to the target protein. The TDs display a high frequency of hydrophobic amino acids necessary for lysosomal membrane anchorage. The motif GXXXXG (purple) located at TD, known as the dimerization motif, is essential for the multimerization of LAMP2A. The TD and CCD domains, as well as the aforementioned critical motifs, exhibit a high degree of conservation across vertebrate species for all three LAMP2 isoforms.