LAUSR

Long noncoding RNAs (lncRNAs) are noncoding RNAs that are ≥200 nucleotides in size and may function in diverse biological processes (1). Although the human genome may encode up to ∼100,000 lncRNAs, most lncRNAs are at low abundance and it is hard to tell their real function. However, a subset of highly expressed lncRNAs are regulatory RNAs with profound functions in the regulation of gene transcription, paraspeckle formation, RNA splicing, messenger RNA (mRNA) stability, and protein degradation (1–3). Most lncRNAs are transcribed by RNA polymerase II and their expression is regulated at both transcription and RNA processing levels (1) and by various virus infections (4, 5). In PNAS, Yang et al. (6) explore the expression profile of cellular lncRNAs in the presence of the histone deacetylase inhibitor Trichostatin A and identify a ∼2-kb-long nuclear lncRNA, ENSG00000273148 or LINC00653, highly expressed from chr20 in p53-null, non–small-cell lung cancer cell line NCI-H1299 cells. Yang et al. (6) show that it regulates lysosomal-associated protein transmembrane 5 (LAPTM5) expression and lysosome cell death (LCD); the authors thus name this lncRNA an LCD regulator, or LCDR. Lysosomes are small cytoplasmic and acidic membrane-bound organelles and contain over 50 hydrolytic enzymes (7) for the digestion of various extraand intracellular materials to maintain cell homeostasis and destroy invading pathogens. Among ∼25 integral lysosomal membrane proteins (8), LAPTM5, which was thought to be specifically expressed in hematopoietic cells (9) to maintain lysosome membrane integrity (8), is also highly expressed in human bladder cancer tissues. Knockdown (KD) of LAPTM5 expression in bladder cancer cell lines T24 and 5637 inhibits cell proliferation and colony formation (10), but the mechanism of LAPTM5 in relation to cell growth function remains unknown. Thus, Yang et al. (6) move one step closer to understanding how LAPTM5 promotes lysosomal membrane integrity and contributes to cancer cell survival, a finding that links LCDR and LAPTM5 as responsible for cytoplasmic lysosomal biogenesis and function. LAPTM5 complementary DNA (cDNA) was cloned in 1996 (9). The LAPTM5 gene on chr1p34 encodes a pre-mRNA containing eight exons, which is processed by nuclear RNA splicing to produce a ∼2.6-kb mRNA and, after RNA export, encode a ∼29-kDa LAPTM5 protein preferentially localized to the lysosome membrane (9, 11) along with other lysosomal proteins, such as LAMP1/2 (8) (Fig. 1). Yang et al. (6) show that among six lysosomal proteins (ACP2, ARSB, ASAH1, GLB1, HGSNAT, and LAPTM5) susceptible to up-regulation by both LCDR and heterogenous nuclear ribonucleoprotein K (hnRNPK), short interfering RNA (siRNA)–mediated reduction of LAPTM5 expression turned out to be the only one causing lysosomal membrane permeabilization (LMP), cell apoptosis, and decreased cell proliferation and colony formation (6). Although all of these results are consistent with the data by KD of LCDR or hnRNPK expression to reduce LAPTM5 expression in NCI-H1299 cells, the observed LAPTM5 function in the regulation of the programmed cell death that was unrelated to other apoptosis-causing genes in Yang et al. (6) is interesting. But the data appear to contradict studies where overexpression of LAPTM5 in neuroblastoma cells was found to cause LMP and nonapoptotic cell death (12) and in HeLa cells to induce cleavage of Mcl-1, Bid, caspases, and PARP, leading to mitochondria-dependent apoptosis (13). How LAPTM5 both at an increased or decreased level induces cell apoptosis and cell death in a celltype–dependent manner remains unknown. Obviously, this contradictory, but interesting, result and some fundamental questions need to be carefully investigated. In the investigation of how nuclear LCDR functions in NCI-H1299 cells to maintain LAPTM5