Disease relevance of MAL2

• MAL2, a novel raft protein of the MAL family, is an essential component of the machinery for transcytosis in hepatoma HepG2 cells [1].
• Alterations in MAL2 expression, distribution, and appearance were found in specific types of follicular cell-derived carcinomas [2].
• Detection of MAL2 significantly increased after infection and it was colocalized with HSV-1 proteins [3].
• Given that MALP-2 has been recently shown to be expressed at the surface of M. fermentans as a molecular entity, sMALP-2 constitutes a valuable surrogate for investigating immunomodulation by these microorganisms and evaluating the role that this activity plays in the development of inflammatory diseases associated with mycoplasma infections [4].
• Anti-inflammatory drugs inhibited MALP-2-mediated bone resorption by about 30% [5].

High impact information on MAL2

• Herein, we present the functional characterization of MAL2, a member of the MAL protein family, in polarized HepG2 cells [1].
• MAL2 greatly colocalized in subapical endosome structures with transcytosing molecules en route to the apical surface [1].
• MAL2 depletion did not affect the internalization of these molecules but produced their accumulation in perinuclear endosome elements that were accessible to transferrin [1].
• MAL2 resided selectively in rafts and is predominantly distributed in a compartment localized beneath the subapical F-actin cytoskeleton [1].
• Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2 [6].

Chemical compound and disease context of MAL2

• We have examined whether toll-like receptor (TLR)2-mediated stimulation by macrophage-activating lipopeptide-2 (MALP-2), originally purified from Mycoplasma fermentans, induces cyclooxygenase (COX)-2 and prostaglandin (PG)E(2) in human placental trophoblast cells [7].

Biological context of MAL2

• The gene MAL2, which was localized to human chromosomal band 8q23 and shown to consist of four exons, is predominantly expressed in human kidney, lung, and liver [8].
• In addition, the specific alterations in MAL and/or MAL2 expression observed in specific types of carcinoma provides a basis to understand the loss of the polarized phenotype that frequently accompanies the neoplastic transformation process [9].
• A significant reduction in TNFalpha-induced apoptosis was demonstrated by stimulation of U937 cells with M. fermentans total proteins, LPMf or MALP-2 (M. fermentans synthetic lipopeptide), but not with M. fermentans hydrophilic protein preparation (AqMf) [10].
• Mycoplasma fermentans lipoproteins and a synthetic lipopeptide, MALP-2, showed cytocidal activity towards HEK293 cells transfected with a TLR2-encoding plasmid [11].
• A gene array experiment suggested that MALP-2 stimulates the release of various mediators involved in wound healing [12].

Anatomical context of MAL2

• MAL2 is predicted to be 176 residues (19 kDa) with four transmembrane domains and is 35.8% identical to MAL, a proteolipid required in apical vesicle transport [8].
• Expression and distribution of MAL2, an essential element of the machinery for basolateral-to-apical transcytosis, in human thyroid epithelial cells [2].
• Herein, we have investigated the expression and distribution of MAL2 in the human thyroid [2].
• Biochemical analysis in primary thyrocyte cultures indicated that MAL2 exclusively resides in raft membranes [2].
• Many different types of specialized secretory cells, either organized in discrete clusters (e.g., endocrine cells in the pancreas) or in endocrine glands (e.g., prostate), were also positive for MAL2 [13].

Associations of MAL2 with chemical compounds

• Most BLP are triacylated at the N-terminus cysteine residue, but mycoplasmal macrophage-activating lipopeptide-2 kD (MALP-2) is only diacylated [14].
• Intriguingly, Pam(3)CSK(4), but not MALP-2 suppressed Ag-induced degranulation of BMMCs (together with early tyrosine phosphorylation and calcium mobilization) in a TLR2-independent manner [15].
• In a coculture with autologous lymphocytes, either MALP-2 or LPS pretreated DC induced a marked proliferation of lymphocytes, but only DC prestimulated with MALP-2 activated lymphocytes to produce the cytokines IL-4, IL-5 and IFN-gamma [16].
• Here we show that an N-ethyl-N-nitrosourea-induced nonsense mutation of Cd36 (oblivious) causes a recessive immunodeficiency phenotype in which macrophages are insensitive to the R-enantiomer of MALP-2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid [17].

Regulatory relationships of MAL2

• The remaining ALS2 allele was placed under control of the C. albicans MAL2 promoter to create an als2Delta/PMAL2-ALS2 strain (named 2342) [18].
• MALP-2 stimulated the liberation of IL-6, while no tumor necrosis factor was detectable [5].

Other interactions of MAL2

• Identification of MAL2, a novel member of the mal proteolipid family, though interactions with TPD52-like proteins in the yeast two-hybrid system [8].
• To understand how transcytosis can be apparently mediated at a distance, we have analyzed the dynamics of machinery and cargo by live-cell imaging of MAL2 and transcytosing CD59, a GPI-anchored protein, in HepG2 cells [19].
• We also identified other novel genes, such as insulin-like growth factor binding protein 5 and a cDNA clone similar to proteolipid MAL2 [20].
• Here we show that TLR6-deficient (TLR6(-/-)) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins [14].
• The effects of inhibitors of NF-kappaB, MEK1/2 and p38 on MALP-2-induced PGE(2) production were also evaluated [7].

Analytical, diagnostic and therapeutic context of MAL2

• Confocal immunofluorescence analysis of thyrocyte cultures revealed that MAL2 predominantly localized in a subapical endosome compartment that was positive for Rab11a [2].
• LPS-mediated cytokine release was studied in mice pretreated with intraperitoneal injections of MALP-2 [21].
• Rather than using recombinant growth factors to accelerate wound healing, we employed the toll-like receptor agonist macrophage-activating lipopeptide-2 (MALP-2) to improve the healing of full-thickness excision skin wounds in an animal model with obese, diabetic mice [12].
• Intranasal vaccination with p17 and the TLR2/6 agonist MALP-2 stimulates strong humoral and cellular immune responses at systemic and mucosal levels [22].
• The migration of neutrophils was enhanced after treatment with MALP-2 [23].

References