MALT-1 shortens lifespan by inhibiting autophagy in the intestine of C. elegans

Abstract

ABSTRACTThe caspase-like protease MALT1 promotes immune responses and oncogenesis in mammals by activating the transcription factor NF-κB. MALT1 is remarkably conserved from mammals to simple metazoans devoid of NF-κB homologs, like the nematode C. elegans. To discover more ancient, NF-κB -independent MALT1 functions, we analysed the phenotype of C. elegans upon silencing of MALT-1 expression systemically or in a tissue-specific manner. MALT-1 silencing in the intestine caused a significant increase in life span, whereas intestinal overexpression of MALT-1 shortened life expectancy. Interestingly, MALT-1-deficient animals showed higher constitutive levels of autophagy in the intestine, which were particularly evident in aged or starved nematodes. Silencing of the autophagy regulators ATG-13, BEC-1 or LGG-2, but not the TOR homolog LET-363, reversed lifespan extension caused by MALT-1 deficiency. These findings suggest that MALT-1 limits the lifespan of C. elegans by acting as an inhibitor of an early step of autophagy in the intestine.Abbreviations: AP-1: activator protein-1; AL: autolysosome; AP: autophagosome; ATG: Autophagy-related gene, BCL10: B cell lymphoma-10; CARD: caspase-recruitment domain; CARMA: CARD-MAGUK, C. elegans: Caenorhabditis elegans; CBM complex: CARMA-BCL10-MALT1 complex; EGFR: epidermal growth factor receptor; ER: endoplasmic reticulum; EV: empty vector; GFP: green fluorescent protein; GPCRs: G-protein coupled receptors; Ig: Immunoglobulin; Int: intestinal; ITAMs: immunoreceptor tyrosine-mediated activation motifs; KO: knock-out; LC3: microtubule-associated protein 1A/1B-light chain 3; LUBAC: linear ubiquitin chain assembly complex; MALT-1: mucosa-associated lymphoid tissue protein-1; NF-κB: nuclear factor-kappa B; NFKI: NF-κB inhibitor; NGM: nematode growth medium; ns: not significant; NS: nervous system; OE: overexpressed; RER: rough endoplasmic reticulum; RNAi: RNA interference; TCR: T cell receptor; TEM: Transmission electron microscopy; TRAF6: TNF receptor-associated factor-6.

Keywords

• Aging
• autolysosome
• autophagosome
• Beclin-1
• chloroquine
• electron microscopy