The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Studies of the similar proteins in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment. In rat hepatic cells, LIMP-2 exhibited a
half-life for internalization and
lysosomal transport of 32 min and 2.0 h, respectively, which resembled those of well-known
lysosomal proteins,
lamp-1 and
lamp-2, though they have different
amino acid sequences in their
cytoplasmic tails. LIMP2 has recently been identified as a novel component of
intercalated discs in
cardiac muscle.
Intercalated discs are composed of
gap junctions,
adherens junctions and
desmosomes, and are critical for the mechanical and electrical coupling of adjacent
cardiomyocytes. The discovery of LIMP-2 as a component of this complex came about from a genetic screen of a homozygous,
hypertensive transgenic rat model of
renin overexpression, in which a population of these rats rapidly develop
heart failure and another remains compensated. Out of 143 differentially-regulated genes, LIMP-2 was identified to be significantly upregulated in
heart failure-prone rat
cardiac muscle biopsies, which also proved true in human
heart failure. Further analysis employing a LIMP-2 knockout mouse demonstrated that animals lacking LIMP-2 failed to flight a normal
hypertrophic response following
angiotensin II treatment, however they developed interstitial
fibrosis and
dilated cardiomyopathy coordinate with disrupted
intercalated disc structure. Biochemical and
immunohistochemical analyses discovered that LIMP-2
interacts with
N-cadherin at
intercalated discs, a function outside of
lysosomal membranes. Knockdown of LIMP-2 with
RNA interference decreased the binding of
N-cadherin to the
phosphorylated form of
beta-catenin, and LIMP-2 overexpression had the reverse effect. LIMP-2 plays other roles in other organs. Characteristic tubular
proteinuria observed in LIMP-2 knockout mice has been shown to be due to a failure of in
lysosomal/
endosomal fusion, thus proteins reabsorbed in the proximal tubule of the kidney are not properly proteolyzed, causing the
proteinuria. Deficiency of LIMP-2 in mice was also reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy. == Clinical significance ==