PSENEN

Official Full Name

presenilin enhancer, gamma-secretase subunit

Organism

Homo sapiens

GeneID

55851

Background

Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer's disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Synonyms

PEN2; PEN-2; MDS033; ACNINV2; MSTP064;

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Detailed Information

The PEN2 gene, officially named PSENEN, is located on human chromosome 19q13.12. It encodes PEN-2, one of the four essential core subunits of the γ-secretase complex. γ-Secretase is a large multi-pass transmembrane protein complex composed of the catalytic subunit presenilin, the scaffold protein APH-1, the auxiliary protein Nicastrin, and PEN-2. PEN-2 is a small, two-pass transmembrane protein that, despite its modest size, is indispensable for the maturation, stability, and enzymatic activity of the complex. Although not part of the catalytic core, PEN-2 is required for assembling fully active γ-secretase. Studies have shown that PEN-2 regulates the ER retention of presenilin, its autocatalytic maturation, and the correct intracellular localization and accumulation of the active complex.

Biological Significance

The biological significance of PEN-2 is inseparable from the function of the γ-secretase complex. γ-Secretase mediates intramembrane proteolysis, cleaving transmembrane proteins within their membrane-spanning regions. This unique activity is central to numerous cellular processes, particularly signal transduction and protein processing. Its most well-known substrates are the amyloid precursor protein (APP) and Notch receptors. Sequential cleavage of APP by γ-secretase generates β-amyloid peptides, especially the aggregation-prone Aβ42, which constitutes the major component of senile plaques in Alzheimer's disease. For Notch receptors, γ-secretase cleavage releases the Notch intracellular domain, which translocates to the nucleus as a transcriptional co-activator to regulate genes controlling cell fate, proliferation, and differentiation. Thus, through its essential role in γ-secretase activity, PEN-2 profoundly influences neural homeostasis and broader developmental processes. Beyond APP and Notch, γ-secretase also processes numerous other substrates, including cadherins and CD44, implicating PEN-2 and the complex in regulating cell adhesion, migration, neurogenesis, and immune responses.

Figure 1. The location of all reported mutations within the c-secretase complex in HS. (Pink AE, et al., 2012)

Clinical Relevance

The clinical significance of PEN2 is linked to γ-secretase's role in two major disease areas: Alzheimer's disease (AD) and Notch pathway–related disorders. In AD, γ-secretase catalyzes the final step in Aβ peptide production and has long been considered a primary target for disease-modifying therapies. However, global γ-secretase inhibitors have repeatedly failed in clinical trials due to strong inhibition of Notch signaling, resulting in severe gastrointestinal and immune toxicities. These challenges have shifted research toward strategies that modulate γ-secretase activity rather than completely inhibit it, or that selectively inhibit APP cleavage while sparing Notch processing. Understanding auxiliary subunits like PEN-2 has become crucial, as they may offer potential targets for fine-tuning complex activity.

Moreover, PEN2 genetic variants have direct disease associations. Loss-of-function mutations in PEN2 cause familial acne inversa (hidradenitis suppurativa, ACNINV2), a chronic inflammatory skin disorder characterized by recurrent abscesses, sinus tracts, and scarring. This condition unexpectedly links γ-secretase function to the development and homeostasis of skin appendages, likely through Notch signaling in hair follicles and sebaceous glands. These findings highlight the physiological importance of PEN-2 in specific tissues and suggest that targeted modulation of local γ-secretase–PEN2 activity could hold therapeutic potential for skin disorders.

References

Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422(6930):438–441.
Prokop S, Shirotani K, Edbauer D, et al. Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. J Biol Chem. 2004;279(20):21255–21265.
Pink AE, Simpson MA, Desai N, et al. Mutations in the γ-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa). J Invest Dermatol. 2012 Oct;132(10):2459-2461.

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