title: Vital function of PRELI and essential requirement of its LEA motif.
abstract: Proteins containing the late embryogenesis abundant (LEA) motif comprise a conserved family, postulated to act as cell protectors. However, their function and mechanisms of action remain unclear. Here we show that PRELI, a mammalian LEA-containing homolog of yeast Ups1p, can associate with dynamin-like GTPase Optic Atrophy-1 (OPA1) and contribute to the maintenance of mitochondrial morphology. Accordingly, PRELI can uphold mitochondrial membrane potential (ΔΨ(m)) and enhance respiratory chain (RC) function, shown by its capacity to induce complex-I/NADH dehydrogenase and ATP synthase expression, increase oxygen consumption and reduce reactive oxygen species (ROS) production. PRELI can also inhibit cell death induced by STS, TNF-α or UV irradiation. Moreover, in vitro and in vivo dominant-negative overexpression of mutant PRELI/LEA(-) (lacking the LEA motif) and transient in vitro PRELI-specific knockdown can render lymphocytes vulnerable to apoptosis, cause mouse embryo lethality and revert the resistance of lymphoma cells to induced death. Collectively, these data support the long-presumed notion of LEA protein-dependent mechanisms of cytoprotection and suggest that PRELI interacts with OPA1 to maintain mitochondria structures intact, sustain balanced ion(-)/proton(+) gradients, promote oxidative phosphorylation reactions, regulate pro- and antiapoptotic protein traffic and enable cell responses to induced death. These findings may help to understand how bioenergetics is mechanistically connected with cell survival cues.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: McKeller
authors.forename: S
authors.initials: S
authors.lastname: Herrera-Rodriguez
authors.forename: W
authors.initials: W
authors.lastname: Ma
authors.forename: B
authors.initials: B
authors.lastname: Ortiz-Quintero
authors.forename: R
authors.initials: R
authors.lastname: Rangel
authors.forename: C
authors.initials: C
authors.lastname: Candé
authors.forename: J C
authors.initials: JC
authors.lastname: Sims-Mourtada
authors.forename: V
authors.initials: V
authors.lastname: Melnikova
authors.forename: C
authors.initials: C
authors.lastname: Kashi
authors.forename: L M
authors.initials: LM
authors.lastname: Phan
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Huang
authors.forename: K
authors.initials: K
authors.lastname: Dunner
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: K K
authors.initials: KK
authors.lastname: Singh
authors.forename: H
authors.initials: H
authors.lastname: Martinez-Valdez
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019069:Cell Respiration; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D017384:Sequence Deletion; D013329:Structure-Activity Relationship
chemical_list: D024101:Mitochondrial Proteins; C487290:PRELI protein, mouse; C102194:PRELID1 protein, human; D011506:Proteins; D020169:Caspases; D020558:GTP Phosphohydrolases