Identification of a Novel Muscle A-type Lamin-interacting Protein (MLIP)

Abstract

Mutations in the A-type lamin (LMNA) gene are associated with age-associated degenerative disorders of mesenchymal tissues, such as dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy. The molecular mechanisms that connect mutations in LMNA with different human diseases are poorly understood. Here, we report the identification of a Muscle-enriched A-type Lamin-interacting Protein, MLIP (C6orf142 and 2310046A06rik), a unique single copy gene that is an innovation of amniotes (reptiles, birds, and mammals). MLIP encodes alternatively spliced variants (23–57 kDa) and possesses several novel structural motifs not found in other proteins. MLIP is expressed ubiquitously and most abundantly in heart, skeletal, and smooth muscle. MLIP interacts directly and co-localizes with lamin A and C in the nuclear envelope. MLIP also co-localizes with promyelocytic leukemia (PML) bodies within the nucleus. PML, like MLIP, is only found in amniotes, suggesting that a functional link between the nuclear envelope and PML bodies may exist through MLIP. Down-regulation of lamin A/C expression by shRNA results in the up-regulation and mislocalization of MLIP. Given that MLIP is expressed most highly in striated and smooth muscle, it is likely to contribute to the mesenchymal phenotypes of laminopathies.

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

“…Because SLC39A8 encodes a zinc transporter [17], its association with DCM may also be related to the cardioprotective role of zinc [18]. In the nuclear envelope, MLIP (also known as CIP) directly interacts with the N-terminal region of lamin (LMNA) [19]. Dominant mutations in LMNA cause DCM and other hereditary multisystemic diseases and several pathogenic mutations of LMNA are located in its MLIP interacting domain [20].…”

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…1C). We previously reported that MLIP was found in the nucleus, interacting with A-type lamin, and in the cytoplasm of mouse C2C12 myoblasts (3). Using the Mlip Ϫ/Ϫ heart as negative control, we further characterized the localization of MLIP in the adult Mlip ϩ/ϩ heart by immunostaining.…”

“…Because MLIP is highly expressed in the heart, where its isoform expression pattern is complex (Ref. 3 and Fig. 1C), we hypothesized that MLIP would have specific functions in myocardial physiology.…”

“…We recently reported the discovery of MLIP (muscle enriched A-type lamin-interacting protein), encoded by a unique and conserved gene, ubiquitously expressed but enriched in the heart and muscles (3). MLIP was originally identified through its interaction with lamin A/C.…”

“…Initial reports suggested that MLIP might play an important role in heart growth and disease (3,6). To define the biological role of MLIP, we developed an Mlip knock-out mouse model (thereafter referred to as Mlip Ϫ/Ϫ mice).…”