Presenilin/γ-Secretase Cleaves CD46 in Response to Neisseria Infection

Abstract

CD46 is a type I transmembrane protein with complement and T cell regulatory functions in human cells. CD46 has signaling and receptor properties in immune and nonimmune cells, many of which are dependent on the expression of cytoplasmic tail (cyt) isoforms cyt1 or cyt2. Little is known about how cyt1 and cyt2 mediate cellular responses. We show that CD46-cyt1 and CD46-cyt2 are substrates for presenilin/γ-secretase (PS/γS), an endogenous protease complex that regulates many important signaling proteins through proteolytic processing. PS/γS processing of CD46 releases immunoprecipitable cyt1 and cyt2 tail peptides into the cell, is blocked by chemical inhibitors, and is prevented in dominant negative presenilin mutant cell lines. Two human pathogens, Neisseria gonorrhoeae and Neisseria meningitidis, stimulate PS/γS processing of CD46-cyt1 and CD46-cyt2. This stimulation requires type IV pili and PilT, the type IV pilus retraction motor, implying that mechanotransduction plays a role in this event. We present a model for PS/γS processing of CD46 that provides a mechanism by which signals are transduced via the cyt1 and cyt2 tails to regulate CD46-dependent cellular responses. Our findings have broad implications for understanding the full range of CD46 functions in infection and noninfection situations.

Opposing Effects of Bacitracin on Human Papillomavirus Type 16 Infection: Enhancement of Binding and Entry and Inhibition of Endosomal Penetration

“…7A, lanes 5 and 6). Comparable results were observed using a similar reporter based on Notch, another ␥-secretase substrate (79). These data show that Bac blocks HPV16 infection via a ␥-secretase-independent mechanism.…”

Emerging roles of the γ-secretase-notch axis in inflammation

“…The roles of CD46 in T cell activation have been thoroughly reviewed by Ni Choileain and Astier (Ni Choileain & Astier, 2012). The presenilin/γ-secretase (PS/γS) proteolysis of CD46 generates immunoprecipitable cytoplasmic tail peptides (cyt1/2) in response to Neisseria infection (Weyand et al, 2010). However, blocking Notch signaling by γ-secretase inhibitors has been found to reduce the type I IFN-independent suppression of IL-5 in human peripheral blood mononuclear cells, indicating that Notch signaling can inhibit IL-5 (Edwards et al, 2013).…”

The very many faces of presenilins and the γ-secretase complex

“…Occurrence of ICDs acting as signaling molecules, affecting gene expression was firstly proved for Notch intracellular domain (NICD), and afterward proposed also for others, such as the APP intracellular domain (AICD) and ICD of CD46 (Beckett et al 2012; Nakayama et al 2011; Weyand et al 2010). Below, however, we will concentrate on other aspects of γ-secretase action.…”