Invariant chain regulates endosomal fusion and maturation through an interaction with the SNARE Vti1b

Abstract

The Invariant chain (Ii, CD74) is a multifunctional regulator of adaptive immune responses and responsible for sorting MHC-I, MHC-II and other Ii-associated molecules to a specific endosomal pathway. When Ii is expressed, endosomal maturation and proteolytic degradation of proteins are delayed and in non-antigen presenting cells the endosomal size increase, but he molecular mechanisms are not known. We identified that a SNARE, Vti1b, is essential for regulating these Ii induced effects. Vti1b binds to Ii and Vti1b is localized at the contact sites of fusing Ii positive endosomes. Furthermore, a tailless Ii that is not internalized from the plasma membrane relocates Vti1b to the plasma membrane. KO of Ii in an antigen presenting cell line was found to speed up endosomal maturation and silencing of Vti1b inhibits the Ii induced maturation delay. Our results suggest that Ii, by interacting with the SNARE Vti1b in antigen presenting cells, direct specific Ii associated SNARE mediated fusion in the early part of the endosomal pathway that lead to a slower endosomal maturation for efficient antigen processing and MHC antigen loading.

The SNARE protein Vti1b is recruited to the sites of BCR activation but is redundant for antigen internalisation, processing and presentation

“…In immune cells, Vti1b has been reported to play a role in lytic granule exocytosis in cytotoxic T cells ( Dressel et al, 2010 ). In addition, it has recently been suggested that Vti1b interacts with the invariant chain of the major histocompatibility complex II (MHCII) and directs the specific membrane fusion events in the early endosomal pathway that allow efficient antigen processing and antigen loading on MHCII ( Margiotta et al, 2021 ). However, no studies have been carried out on Vti1b in B cells.…”

Hyperthermia based individual in situ recombinant vaccine enhances lymph nodes drainage for de novo antitumor immunity

“…With the extension of incubation time, green fluorescence was overflowed from red lysotracker at 8 h, indicating that these NPs escaped from endo/lysosomes, which was important for SV to exert its adjuvant effect. It is well known that Rab5 expressed early endosomes mature through acidification and material exchange to form Rab7a expressed late endosomes 43 , 44 . After treatment with AuNCs/TDPAs and AuNCs/SV/TDPAs, the expression of Rab5 and Rab7a were observed by CLSM.…”

The Autophagy Receptor TAX1BP1 (T6BP) is a novel player in antigen presentation by MHC-II molecules

“…To this regard, it is interesting to note that we identified in the interactome of T6BP, ATP6V0A1 a subunit of the vATPase that plays a critical role in mediating vesicular acidification (Forgac, 2007). On the other hand, CD74 has been shown to play, by itself, a role in endosomal membrane trafficking (Margiotta et al , 2020; Romagnoli et al , 1993) and perhaps in proteolysis of antigens (Schröder, 2016). It was recently reported that CD74 p41 isoform interacts with cathepsins and regulates their activity in endosomes (Bruchez et al , 2020).…”