Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Abstract

The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also find LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated β-catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect.Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.

Regulation of Cardiac Gene Expression by KLF15, a Repressor of Myocardin Activity

“…Animal Models-Ren-2 rats were obtained from Möllegard Breeding Center, Lille Skensveld, Denmark, and were studied as described previously (20).…”

“…We obtained cardiac biopsies at a time when all Ren-2 rats displayed similar cardiac hypertrophy and were well compensated. After cardiac biopsies were taken, we followed each rat to see whether it would progress to failure or not (20). This revealed that KLF15 expression was decreased significantly more in the hypertrophied hearts that later progressed toward failure (Fig.…”

Lysosomal integral membrane protein-2: A new player in lysosome-related pathology

“…An interesting and unexpected role of LIMP-2 is its involvement in the intercalated disc [25]. In cardiac muscle, intercalated discs connect individual cardiomyocytes, enabling them to function as a unified organ.…”

“…The spectrum of manifestations associated with LIMP-2 expanded further in 2007, when LIMP-2 was identified as a regulator of the cardiac intercalated disc in humans [25]. That same year, LIMP-2 was identified as a receptor for GCase [20].…”

Cell–cell junction remodeling in the heart: Possible role in cardiac conduction system function and arrhythmias?

“…Adherens junctions are mainly composed of fascia adhaerentes/fascia adherens junctions (Franke et al, 2009) which, in cardiac tissue, are formed by membrane spanning cadherins (N-cadherin) linking the actin microfilaments at the cytoplasmic end with cadherins from the neighboring cell at the extracellular end. The molecular components of fascia adherens junctions in cardiac muscle include the (i) main transmembrane protein N-cadherin (~88 kDa), as well as other more recently identified transmembrane and catenin-binding proteins: Coxsackievirus and adenovirus receptor (CAR; ~40 kDa) and lysosomal integral membrane protein 2 (LIMP-2; ~54 kDa) (Lim et al, 2008; Schroen et al, 2007), (ii) the catenins/armadillo proteins, α, β and γ (plakoglobin)-catenin (~102, ~88 and ~82 kDa respectively) as well as (iii) the cytoskeletal actin-binding proteins, vinculin/metavinculin (~117/124 kDa), zonula occludens-1 (ZO-1; ~220 kDa), Xin repeat containing protein, mXinα (~155 kDa) and α-actinin (~110 kDa) (Borrmann et al, 2006; Choi et al, 2007; Franke, 2009; Gutstein et al, 2003; Itoh et al, 1997; Sheikh et al, 2006). Desmosomes ( maculae adhaerentes ) are considered the strongest anchoring junctions and are formed by specialized cadherins (desmocollin-2 ~100 kDa and desmoglein-2 ~122 kDa in the heart) of neighboring cells that bind to one another at the extracellular end (Franke, 2009).…”