Karolinska Research Lectures – Keiji Tanaka

//Karolinska Research Lectures – Keiji Tanaka

Keiji Tanaka
Title:“Basic Mechanisms and Physiopathological Roles of Eukaryotic Proteasomes”
Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Date:September 18, Thursday, 16.15
Location:Nobel Forum
Host: Lorenz Poellinger
Contact:Tatiana Goriatcheva, Nobelkansliet, Nobel Forum, tel:+46-8-52487805,

The proteasome is a 2.5-MDa sophisticated multisubunit complex that contains a catalytic core particle (CP) and two terminal regulatory particles (RPs), which associate with the termini of the central CP at opposite orientations. The CP consists of four heptameric rings (two outer a-rings and two inner b-rings), which are made up of seven structurally related, but not identical, a and b subunits. The CP contains catalytic threonine residues (b1, b2, and b5 with caspase-like, trypsin-like, and chymotrypsin-like activities, respectively) on the surface of a chamber formed by two abutting b-rings. The RP recognizes polyubiquitylated substrate proteins and then unfolds and translocates these proteins into the interior of the CP for degradation. The RP comprises 19 different subunits, which are thought to form two subcomplexes called the lid and the base. It is a longstanding question how the complex structure of the proteasome is organized with high fidelity. During the past decade, a growing body of evidence has revealed the molecular mechanisms underlying proteasome assembly. Recently, we identified a restricted set of proteasome-dedicated assembling chaperones

[i.e., proteasome assembling chaperones (PAC) 1-4 and RP assembling chaperones (RAC) 1-4] that assist in the efficient formation of the proteasome, proposing a novel model in which multiple dedicated chaperones govern proteasome assembly. In addition, quantitative live-cell imaging revealed spatio-temporal dynamics and cytoplasmic assembly of the proteasome. On another front, we discovered two immuno-type proteasomes, the immunoproteasome and the thymoproteasome, whose catalytic subunits are replaced by homologous counterparts. These two isoforms perform specialized functions that discriminate self from non-self in cell-mediated immunity; i.e., they function as enzymes that process intracellular antigens for cytotoxic T-lymphocyte (CTL) responses and thymic positive selection. Moreover, emerging evidence suggests that the proteasome plays an important role in various intractable diseases that have been increasing in today’s aging society.