PARL

Official Full Name

presenilin associated rhomboid like

Organism

Homo sapiens

GeneID

55486

Background

This gene encodes a member of the rhomboid family of intramembrane serine proteases that is localized to the inner mitochondrial membrane. The encoded protein regulates mitochondrial remodeling and apoptosis through regulated substrate proteolysis. Proteolytic processing of the encoded protein results in the release of a small peptide, P-beta, which may transit to the nucleus. Mutations in this gene may be associated with Parkinson's disease. [provided by RefSeq, May 2016]

Synonyms

PSARL; PSARL1; RHBDS1; PRO2207; PSENIP2;

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Detailed Information

The role of PARL in the way to apoptosis

The mitochondrial inner membrane rhomboid peptidase PARL is known to be involved in critical signaling cascades, but its role in the way to apoptosis is still not fully understood. In recent studies, PARL was demonstrated to be able to process the mitochondrial pro-apoptotic protein Smac, which can antagonize XIAP-mediated caspase inhibition since its release into the cytosol, to promote apoptosis. Within transmembrane domains, the mitochondrial intramembrane peptidase PARL cleaves its substrates to take part in crucial mitochondrial signaling cascades, including mitophagy via processing of the PINK1 and PGAM5, in detail, PINK1 topogenesis between the inner and outer mitochondrial membranes were controlled and CJs were stabilized via OPA1 processing to hinder apoptosis. Proteomic approaches were used to search for PARL substrates in wild-type and PARL knockout human cells, and mitochondrial proteins Smac, TTC19, CLPB and STARD7, the previously established substrates PINK1 and PGAM5, were identified. The functional and mechanistic characterization of PARL-dependent processing of the mitochondrial IM protein Smac was demonstrated to be a pro-apoptotic protein, which is released into the cytosol to relieve caspase activities from the XIAP inhibition for apoptosis. Bax-Bak-induced MOMP mediates the PARL-cleaved Smac fragment releasing into the cytosol. This processing was found to able to allow the Smac fragment bind to XIAP to prevent XIAP-mediated caspase inhibition by generating an N-terminal XIAP-binding motif.

PARL deficiency in mice causes complex III defects, coenzyme Q depletion, and Leigh-like syndrome

In vitro assays of the mitochondrial intramembrane rhomboid protease PARL, it has been confirmed to be implicated in diverse functions, while its physiological role in vivo remains unclear. Nervous system conditional PARL deficient mice have a similarity with germline Parl KOs in phenotype, outlining the significance of PARL in neurological homeostasis. More than this, modification of this severe neurological phenotype cannot occur after genetically modifying the two major PARL substrates, PINK1 and PGAMS. Four factors can answer how Parl^-/- brain mitochondria are affected, including progressive ultrastructural changes, defects in complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL works as a necessity for the stable expression of TTC19, which is required for CIII activity, and of COQ4, to function in CoQ biosynthesis. Maintenance of the respiratory chain in the nervous system partially relies on the function of PARL, deficiency of which causes progressive mitochondrial dysfunction and structural abnormalities, giving rise to neuronal necrosis and leigh-like syndrome.

Figure 1. PARL protease: A glimpse at intramembrane proteolysis in the inner mitochondrial membrane. (Laine Lysyk, et al. 2020)

References:

Lysyk L, Brassard R, Touret N, et al. PARL protease: A glimpse at intramembrane proteolysis in the inner mitochondrial membrane. Journal of Molecular Biology, 2020, 432(18): 5052-5062.
Ishihara N, Mihara K. PARL paves the way to apoptosis. Nature Cell Biology, 2017, 19(4): 263-265.
Spinazzi M, Radaelli E, Horré K, et al. PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome. Proceedings of the National Academy of Sciences, 2019, 116(1): 277-286.

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